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Physiol Rev 95: 1– 46, 2015 doi:10.1152/physrev.00012.2014

MAGNESIUM IN MAN: IMPLICATIONS FOR HEALTH AND DISEASE Jeroen H. F. de Baaij, Joost G. J. Hoenderop, and René J. M. Bindels Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands De Baaij JHF, Hoenderop JGJ, Bindels RJM. Magnesium in Man: Implications for Health and Disease. Physiol Rev 95: 1– 46, 2015; doi:10.1152/physrev.00012.2014.—Magnesium (Mg2⫹) is an essential ion to the human body, playing an instrumental role in supporting and sustaining health and life. As the second most abundant intracellular cation after potassium, it is involved in over 600 enzymatic reactions including energy metabolism and protein synthesis. Although Mg2⫹ availability has been proven to be disturbed during several clinical situations, serum Mg2⫹ values are not generally determined in patients. This review aims to provide an overview of the function of Mg2⫹ in human health and disease. In short, Mg2⫹ plays an important physiological role particularly in the brain, heart, and skeletal muscles. Moreover, Mg2⫹ supplementation has been shown to be beneficial in treatment of, among others, preeclampsia, migraine, depression, coronary artery disease, and asthma. Over the last decade, several hereditary forms of hypomagnesemia have been deciphered, including mutations in transient receptor potential melastatin type 6 (TRPM6), claudin 16, and cyclin M2 (CNNM2). Recently, mutations in Mg2⫹ transporter 1 (MagT1) were linked to T-cell deficiency underlining the important role of Mg2⫹ in cell viability. Moreover, hypomagnesemia can be the consequence of the use of certain types of drugs, such as diuretics, epidermal growth factor receptor inhibitors, calcineurin inhibitors, and proton pump inhibitors. This review provides an extensive and comprehensive overview of Mg2⫹ research over the last few decades, focusing on the regulation of Mg2⫹ homeostasis in the intestine, kidney, and bone and disturbances which may result in hypomagnesemia.

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INTRODUCTION MAGNESIUM IN CELLULAR PHYSIOLOGY REGULATION OF MAGNESIUM ... MAGNESIUM IN PHYSIOLOGY AND ... DISTURBANCES OF MAGNESIUM ... CONCLUDING REMARKS

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I. INTRODUCTION Magnesium (Mg2⫹) is an essential ion for health. Mg2⫹ plays an important role in the physiological function of the brain, heart, and skeletal muscles. Mg2⫹ has anti-inflammatory properties and acts as Ca2⫹ antagonist. The United States Food and Nutrition Board recommends a daily intake of 420 mg for men and 320 mg for women (1). However, recent reports estimate that at least 60% of Americans do not consume the recommended daily amount of Mg2⫹ (281). Part of the problem stems from the soil used for agriculture, which is becoming increasingly deficient in essential minerals. Over the last 60 years the Mg2⫹ content in fruit and vegetables decreased by 20 –30% (570). Moreover, the Western diet contains more refined grains and processed food. Estimates are that 80 –90% of Mg2⫹ is lost during food processing. As a result, a significant number of people are Mg2⫹ deficient, which may comprise up to 60%

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I. II. III. IV. V. VI.

of critically ill patients (84, 145). Mg2⫹ deficiency is commonly determined by measuring total serum Mg2⫹ concentrations, which ranges between 0.7 and 1.05 mM in a healthy person (323). However, serum Mg2⫹ values reflect only 1% of the body Mg2⫹ content, since most of the body’s Mg2⫹ is stored in bone, muscle, and soft tissues. Therefore, although serum values are within the normal range, the body can be in a severely Mg2⫹-depleted state. Consequently, the clinical impact of Mg2⫹ deficiency may be largely underestimated. The first use of Mg2⫹ in human medicine can be traced back to 1697 when Dr. Nehemiah Grew identified magnesium sulfate (MgSO4) as the major ingredient of Epsom salt (195). Epsom salt was extracted from a well in Epsom, England and was used over the years to treat abdominal pain, constipation, sprains, muscle strains, hyaline membrane disease, and cerebral edema. Subsequently, Mg2⫹ was recognized as an element (Mg) by Joseph Black in 1755 and first isolated by Sir Humphrey Davy from magnesia [Mg3SO4O10(OH)2] and mercury in 1808 (102). The role of Mg2⫹ in the human body emerged once Mg2⫹ was described in blood plasma by Willey Glover Denis in 1920 (113). In 1926, Jehan Leroy demonstrated that Mg2⫹ is essential for life in mice (309). These findings were trans-

0031-9333/15 Copyright © 2015 the American Physiological Society

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MAGNESIUM IN MAN lated to humans, and the first report of Mg2⫹ deficiency in humans was by Arthur Hirschfelder and Victor Haury in 1934 (231). Since then, Mg2⫹ has been implicated in and used for treatment of a variety of diseases, including migraines, cardiovascular diseases, and diabetes. Although the importance of Mg2⫹ is widely acknowledged, serum Mg2⫹ values are not generally determined in clinical medicine. Therefore, Mg2⫹ is often referred to as the “forgotten” cation in human health.

in practically every major metabolic and biochemical process within the cell. Although it extends beyond the purpose of this review to give a comprehensive overview of all biochemical reactions and structural processes involving Mg2⫹, the following paragraphs will highlight the most prominent cellular processes in which Mg2⫹ is involved.

This review provides an overview of the role of Mg2⫹ in human health and disease. Mg2⫹ has important cellular functions in enzymatic reactions and in the synthesis and structure of proteins and polynucleotides, which are described in section II. The important regulation of Mg2⫹ homeostasis is discussed in depth in section III. The role of Mg2⫹ in organ function and related diseases is discussed in section IV. An overview is presented of the most important diseases in which Mg2⫹ disturbances have been implicated or in which Mg2⫹ has been considered as a potential treatment. In last part of the review, special attention is awarderd to disturbances of intestinal Mg2⫹ uptake and renal Mg2⫹ excretion (sect. V). All together, this review emphasizes the importance of a controlled Mg2⫹ balance in the human body. Increasing the awareness and understanding of Mg2⫹ homeostasis may give more clinical attention to the important role of Mg2⫹ in health and disease.

Mg2⫹ forms an essential component of the RNA and DNA tertiary structures, as it binds the negatively charged O and N molecules within the polynucleotide chains. Polynucleotide binding is a complex biophysical process that mainly depends on the level of Mg2⫹ dehydration and the electrostatic potential at the binding site (for extensive review, see Ref. 347). The most studied Mg2⫹-RNA interaction is tRNA, where Mg2⫹ stabilizes the structure. The role of Mg2⫹ became evident in 1966, when it was shown that Mg2⫹ could restore denaturated tRNA molecules (319). Crystallographic structures of tRNAs from yeast identified five Mg2⫹-binding sites, three in the core region around the bend of the L-shaped molecule and two additional sites in the major groove of the anticodon stem (412, 556). Additionally, there may be a few dozen Mg2⫹ in close vicinity of tRNA molecules that may bind weakly to the exterior of the structure (347). Still, the importance of Mg2⫹ binding for the tRNA tertiary structure has been contested over the years. This discussion was mainly triggered by studies showing the importance of nonspecific diffuse binding of Mg2⫹ and other divalent and monovalent cations, questioning the specificity of the Mg2⫹ interactions. However, the role of Mg2⫹ in RNA structure extends beyond tRNAs. For instance, Mg2⫹ is also crucial to the interactions that stabilize the pseudoknot conformation (191), tertiary RNA structures that are present in mRNA, ribosomal RNA, transfer-messenger RNA, catalytic self-splicing RNA, and viral genomic RNA.

Within the periodic table of elements, Mg has the atomic number 12 and is classed as an alkaline earth element (group 2). Mg occurs in three stable isotopes: 24Mg, 25Mg, and 26Mg. 24Mg is the most common isotope (78,99%) and has a relative atomic mass of 24.305 Da, a melting point of 648.8°C, and a boiling point of 1,090°C (350). Mg2⫹ is highly soluble and the second most abundant cation in seawater (95). In the dissolved state, Mg2⫹ has two hydration shells, making its hydrated radius ⬃400 times larger than its dehydrated radius, larger than that of other cations like Na⫹, K⫹, and even Ca2⫹ (95). Consequently, Mg2⫹ needs to be dehydrated before passing through channels and transporters, a process that requires a lot of energy. Mg2⫹ is a powerful Ca2⫹ antagonist, despite both having similar charge and chemical properties. Mg2⫹ is the second most abundant intracellular cation with typical concentrations of ⬃10 –30 mM. However, since most of the intracellular Mg2⫹ is bound to ribosomes, polynucleotides and ATP, the concentration of freely available Mg2⫹ falls within the low millimolar range (0.5–1.2 mM) (133). In contrast to other abundant ions, for which cells maintain considerable transmembrane gradients, the free Mg2⫹ concentrations in the cell and in the extracellular fluid are comparable. Mg2⫹ is a versatile ion that is involved

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In DNA, Mg2⫹ forms hydrogen bonds with the electronegative elements (O, N) to stabilize the natural DNA conformation, referred to as B-DNA (85, 549). Moreover, Mg2⫹ plays a role in the secondary and tertiary structure of DNA by competing with monovalent ions (394). Mg2⫹ binds the minor groove of B-DNA structures, thus protecting it. In Mg2⫹-deficient conditions, DNA is more accessible to free oxygen radicals and more prone to oxidative stress (406). However, at higher Mg2⫹ concentrations, Mg2⫹ may covalently bind DNA, locally distorting the double helix (22). Therefore, maintaining the cellular Mg2⫹ concentration within the physiological range is essential for DNA stability.

B. Enzymatic Activity In medical textbooks and scientific literature, Mg2⫹ is often described as a cofactor for ⬃300 enzymes. Theodor

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II. MAGNESIUM IN CELLULAR PHYSIOLOGY

A. Nucleotide Binding


DE BAAIJ ET AL. Günther introduced the number 300 as a rough estimate in 1980 and this has been in use ever since (133). However, in the decades after 1980 many new Mg2⫹-dependent enzymes have been described, and the number 300 is, therefore, an underestimation. Currently, enzymatic databases list over 600 enzymes for which Mg2⫹ serves as cofactor, and an additional 200 in which Mg2⫹ may act as activator (32, 73). An overview of these Mg2⫹-dependent enzymes can be found at MetaCyc (http://www.metacyc.org; Ref. 73). Many of the enzymes that require Mg2⫹ as coactivator are vital for life.

Mg2⫹ is also an important regulator of many enzymes involved in glycolysis, because it is a cofactor for adenine nucleotides. Mg-ATP is required for the activity of hexokinase, phosphofructokinase, aldolase, phosphoglycerate kinase, and pyruvate kinase (166, 550). Consequently, Mg2⫹ availability is of major importance for glucose metabolism, which may explain its role in diabetes mellitus type 2 (see sect. IVE1). The role of Mg2⫹, however, extends far beyond DNA and protein synthesis, DNA repair, and glycolysis. Since kinases, ATPases, guanylyl cyclases, and adenylyl cyclases all depend on Mg-ATP for proper function, Mg2⫹ plays a role in virtually every process in the cell.

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Mg2⫹ is necessary for the proper structure and activity of DNA and RNA polymerases (56, 500). DNA polymerases have two Mg2⫹ binding sites, which are hypothesized to play a key role in the conformational changes in the polymerase enzyme during the catalytic reaction (56). This model was further enhanced by studies reporting that the release of one of the Mg2⫹ions is necessary for opening the catalytic site for new nucleotides (577). In addition, Mg2⫹ is an important factor in DNA repair mechanisms within the cell, including nucleotide excision repair (NER), base excision repair (BER), and mismatch repair (MMR). Mg2⫹ acts as cofactor for almost every enzyme involved in basically every step of NER (68). In BER, Mg2⫹ is elemental for the activity of endonucleases, which incise the DNA after DNA damage, and the DNA polymerases and ligases, which repair the gap (41, 473). The third repair pathway, MMR, is also affected by Mg2⫹ availability since several enzymes involved require Mg2⫹ and ATP for activity (33). Other enzymes requiring Mg2⫹ are topisomerases, helicases, exonucleases, protein kinases, cyclases, and large groups of ATPases, meaning that Mg2⫹ is an essential component of

DNA replication, RNA transcription, amino acid synthesis, and protein formation. Altogether, Mg2⫹ is a key factor in the maintenance of genomic and genetic stability. The consequences of low Mg2⫹ availability on the development of cancer is discussed in section IIE1.

Since protein and DNA synthesis are highly dependent on intracellular Mg2⫹ availability, intracellular Mg2⫹ concentrations are tightly regulated. Over the last 20 years, elucidating the molecular identities of the transporters involved in Mg2⫹ homeostasis has been the main focus of research within the Mg2⫹ field. Genetic screenings on human diseases and microarray-based expression studies have resulted in the identification of numerous Mg2⫹-transporting proteins (TABLE 1 and FIGURE 1). Although the exact role of many of these proteins needs further investigation, re-

Table 1. Mg2⫹ Transporters Name

Membrane

Expression

Permeability

Mechanism

Disease

Reference Nos.

General Mg2⫹ transporters TRPM7 MagT1 SLC41A1

Plasma membrane Plasma membrane Plasma membrane

Ubiquitous Ubiquitous Ubiquitous

Ba⬎Ni⬎Mg⬎Ca Mg⬎Ba⬎Fe⫽Cu Mg⬎Sr⬎Fe⬎Ba⬎Cu

Channel Channel Exchanger

SLC41A2 CNNM3 MRS2

Golgi membrane Plasma membrane Mitochondrial membrane

Ubiquitous Ubiquitous Ubiquitous

Mg⬎Ba⬎Ni⬎Ca Mg⬎Fe⬎Cu⬎Co Mg⬎Ni

Exchanger Transporter? Channel

X-MEN syndrome Nephronophthisis-like

314, 349 187, 311 185, 251, 289 442 545 399

Tissue-specific Mg2⫹ transporters TRPM6 CNNM1 CNNM2 CNNM4

Apical plasma membrane Kidney, intestine ? Brain Basolateral plasma Kidney membrane Basolateral plasma Intestine membrane

Ba⬎Ni⬎Mg⬎Ca

Channel

Cu⬎Mg? Mg⬎Sr⬎Zn⬎Cd

? Transporter? Sensor? Exchanger?

Mg

Hypomagnesemia secondary hypocalcemia Hypomagnesemia with seizures and mental retardation Jallili syndrome

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314 13, 545 184, 497 387, 402, 575

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searchers have identified several proteins critical to cellular Mg2⫹ homeostasis. Within this part of the review, we will focus on the ubiquitous transporters transient receptor potential melastatin type 7 (TRPM7), Mg2⫹ transporter 1 (MagT1), and solute carrier family 41 member 1 (SLC41A1). Tissuespecific Mg2⫹ transporters such as transient receptor potential melastatin type 6 (TRPM6; kidney, colon), cyclin M2 (CNNM2; kidney) and cyclin M4 (CNNM4; colon) are discussed in section III. 1. TRPM7 TRPM7 is a ubiquitously expressed divalent cation channel that is responsible for much of the Mg2⫹ flux in the cell. TRPM7 activity is generally regarded as a prerequisite for cell viability (360, 455). However, recent reports with tissue-specific TRPM7 KO mice suggest that TRPM7-deficient T cells are still viable and have normal intracellular

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Mg2⫹ concentrations (266). TRPM7 constitutes a tetrameric channel, where each subunit consists of six transmembrane regions with a pore region between the fifth and sixth transmembrane domain (42). The intracellular COOH terminus contains a kinase domain that regulates autophosphorylation of the channel, although its mechanism is poorly understood, as TRPM7 channel function is not dependent on its kinase activity (504). Initially, the kinase was reported to exist as separate entity (438), and indeed, recently it was shown that the kinase is cleaved from TRPM7 by caspase-8, although the exact function of the cleaved kinase remains unknown (115). 2. MagT1 Originally identified in MDCT cells, Mg2⫹ transporter 1 (MagT1) has been described as a ubiquitously expressed Mg2⫹ channel (187). Survival and growth of TRPM7-defi-

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FIGURE 1. Magnesium in cellular physiology. Cellular Mg2⫹ homeostasis is regulated by the combined action of TRPM7, SLC41A1, MagT1, and CNNM3 Mg2⫹ transporters. MRS2 transporters regulate intramitochondrial Mg2⫹ concentrations. In the nucleus, Mg2⫹ is involved in DNA stability and DNA repair and regulates the activity of the DNA and RNA polymerases. Within the cell cytosol, Mg2⫹ regulates ATP binding, enzymatic activity of more than 600 enzymes, proliferation, and tRNA and mRNA stability. Activation of growth factor receptors, such as the EGFR, will increase Mg2⫹ uptake and release of membrane-bound Mg2⫹ resulting in mTOR activation and Ca2⫹ release from the ER. These mechanisms are essential for cell growth and proliferation. TRPM7, transient receptor potential melastatin type 7; CNNM3, cyclin M3; SLC41A1, solute carrier family 41 type 1; MagT1, magnesium transporter 1; MRS2, mitochondrial RNA splicing 2; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; PLC␥, phospholipase C-␥; PIP3, phosphatidylinositol 3,4,5-trisphosphate; IP3, inositol trisphosphate.


DE BAAIJ ET AL. cient cells can be partially rescued by MagT1 overexpression (110). Although identification of MagT1 dates back almost 10 years, the functional characteristics of MagT1 are still undetermined. MagT1 mediates highly specific Mg2⫹ currents in Xenopus laevis oocytes, but these results could not be reproduced in mammalian cells (187, 589). Recent studies in T cells suggest that MagT1 mediates a rapid Mg2⫹ influx upon receptor activation (79, 311). Since T cells do not require TRPM7 for maintaining normal intracellular Mg2⫹ concentrations (266), this suggests that MagT1 has a similar function as TRPM7 in certain cell types.

CNNM1 is mainly expressed in brain, CNNM2 expression is high in kidney, and CNNM4 is primarily expressed in intestine (105). In contrast, CNNM3 has a ubiquitous expression pattern and may play a role in the maintenance of cellular Mg2⫹ homeostasis. A recent study shows that CNNM3 transports Mg2⫹, and its activity is regulated by oncogene PRL2 (217). The interaction between PRL2 and CNNM3 is essential for Mg2⫹ influx that drives tumor growth. Therefore, CNNM3 should be considered in future studies on cellular Mg2⫹ handling in nonpathological conditions. 6. MRS2

3. Extrusion Although most studied in yeast, MRS2 (mitochondrial RNA splicing 2) is considered to be the primary Mg2⫹ channel on the mitochondrial membrane (592). Knockdown of MRS2 results in reduced Mg2⫹ uptake in mitochondria and cell death (399). Using the newly developed mitochondrial Mg2⫹ fluorescent probe KMG-301, Shindo et al. (475) revealed that MRS2 regulates intramitochondrial Mg2⫹ concentrations. This finding is interesting, since it indicates that mitochondria may store intracellular Mg2⫹. Given that Mg2⫹ is of major importance for ATP binding, intramitochondrial Mg2⫹ concentrations may indirectly influence the progression of the citric acid cycle. Recently, it was shown that MRS2 mutations cause demyelination. The relevance of this observation to Mg2⫹ homeostasis still remains to be determined (296).

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In 1984, Theodor Gunther et al. (214) proposed that the main route of Mg2⫹ efflux from the cell is Na⫹ dependent. A large body of evidence obtained in a wide range of cell types supports this notion (reviewed in Ref. 424). Over the last decades, the mechanism has been further characterized in a variety of cell types, demonstrating inhibition by Na⫹ channel blockers such as amiloride, imipramine, and quinidine. The stoichiometry of this exchange mechanism is still not fully elucidated; Na⫹-dependent Mg2⫹ extrusion is activated by cAMP in several cell models and conditions (424), but Na⫹-independent Mg2⫹ extrusion has also been proposed. Ebel et al. (134) reported the presence of a choline-dependent Mg2⫹ transporter in erythrocytes. However, the molecular identity of this proposed Mg2⫹ efflux mechanism remains controversial.

7. Others

4. SLC41A1 Recent reports by Kolisek and co-workers (288, 289) suggested that solute carrier family 41 member 1 (SLC41A1) functions as a Na⫹/Mg2⫹ exchanger with a 2:1 stoichiometry. SLC41A1 contains 11 transmembrane domains and was originally described as a Mg2⫹ transporter mediating Mg2⫹ currents in Xenopus laevis oocytes (185). Although electrophysiological analysis could not confirm these measurements in mammalian cells, Mg2⫹ efflux studies using mag-fura 2 show Na⫹-dependent Mg2⫹ extrusion (251, 289). Gain-of-function SNPs have been associated with Parkinson’s disease, and one mutation in SLC41A1 was identified in a patient with a nephronophthisis-like phenotype (251, 290, 576). SLC41A1 is part of a larger protein family including two additional members, SLC41A2 and SLC41A3, which are studied less extensive. Although SLC41A2 was initially described as a plasma membrane protein, it has a topology opposite to SLC41A1 (442). This finding suggests that SLC41A2 might be expressed on the membranes of organelles and may be involved in subcellular Mg2⫹ transport. 5. CNNM3 Members of the Cyclin M (CNNM) family have been proposed to function as Mg2⫹ transporters (184, 545).

In addition to the aforementioned Mg2⫹ transporters, several other proteins have been proposed to transport Mg2⫹. However, these claims are based mainly on overexpression in the Xenopus oocytes model, and functional evidence for these proteins is scarce. For example, the nonimprinted in Prader-Willi/Angelman syndrome (NIPA) family of proteins has been proposed to transport Mg2⫹, based on Mg2⫹ currents in Xenopus laevis oocytes (182), but recent studies indicate that NIPA proteins have a role in bone morphogenetic protein (BMP) signaling (525). Likewise, Huntingtininteracting protein 14 (HIP14) was thought to mediate Mg2⫹ fluxes at the Golgi membrane (183). Now it has become apparent that its main function consists of palmitoyl acyltransferase activity, specifically involved in the palmitoylation of Huntington (129, 582). Therefore, the role of NIPA proteins and HIP14 in Mg2⫹ transport should be questioned. Additionally, members of the membrane Mg2⫹ transporter (MMgT) family have been shown to transport divalent cations in Xenopus oocytes (186). However, as they have only one transmembrane domain after signal peptide cleavage, it is unlikely that they form functional Mg2⫹ transporters themselves. It is possible that MMgT proteins may form subunits of other Mg2⫹ channels, and as a consequence, future studies should be directed to the identification of its protein partners.

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D. Cell Signaling Mg2⫹ acts as a physiological Ca2⫹ antagonist within cells, and as a result, the Mg2⫹/Ca2⫹ ratio is of major importance for the activity of Ca2⫹-ATPases and other Ca2⫹ transporting proteins (257). Small changes in the Mg2⫹ availability within the cell may therefore cause disturbed Ca2⫹ signaling or Ca2⫹ toxicity.

E. Cell Proliferation Given its effect on RNA, DNA, and protein synthesis, Mg2⫹ is an important factor in the control of cell proliferation. Over the last 40 years, the role of Mg2⫹ in cell cycle control, protein synthesis, and growth factor response has been extensively studied, pioneered by several groundbreaking studies from the group of Harry Rubin (428, 430). Cell proliferation is largely dependent on protein synthesis, more than DNA or RNA synthesis. Inhibition of protein synthesis directly shuts down DNA synthesis, whereas there is a 2-h delay to achieve the same effect using RNA synthesis inhibitors (279). Protein synthesis is highly dependent on intracellular Mg2⫹ concentrations; increasing the Mg2⫹ content amplifies protein synthesis within 60 min, whereas DNA synthesis is only enhanced after 10 h (429, 514). Activation of proliferation is initiated by growth factors that increase glucose uptake and protein synthesis within minutes (225). Interestingly, Mg2⫹ is tightly regulated during these intracellular processes. Initial studies in cultured

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1. Cancer Tumor cells contain high concentrations of intracellular Mg2⫹ (508). In a mammary tumor cell line, Mg2⫹ can be transported into the cell even when extracellular Mg2⫹ concentrations were below physiological levels (203, 264, 566). Mg2⫹ uptake via divalent cation channel TRPM7 has been suggested to stimulate tumor cell proliferation (203, 264). TRPM7 expression is upregulated in hepatoma, pancreatic adenocarcinoma, gastric cancer, and breast cancer tissue (203, 278, 346, 581). Although TRPM7 has been primarily described as a Mg2⫹ channel, it is also permeable for other divalent cations (349). Given the involvement of Mg2⫹ in cell proliferation, the influx of Mg2⫹ via TRPM7 has been proposed as the main regulator of tumor growth. However, recent studies using prostate cancer cells suggest that TRPM7-mediated Ca2⫹ uptake may also play an important role in tumor growth (501). The expression of Mg2⫹ transporter CNNM3 is increased in human breast cancer tissue (217). CNNM3 binds oncogene PRL2 and facilitates the entry of Mg2⫹ in the tumor cell to drive cell proliferation. Elevated intracellular Mg2⫹ concentrations have been suggested to be beneficial for tumor growth because Mg2⫹ regulates several cancer-associated enzymes including telomerase and protein phosphatase 1D, which are involved in the glycolytic cycle and BER (74). However, the regulatory role of Mg2⫹ on these enzymes during the pathogenic state of tumor cell proliferation has never been inves-

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Since 1974, when Mg2⫹ influx was detected upon insulin stimulation, several groups have suggested a second messenger role for Mg2⫹ (311, 322, 503). Most recently in a study on T-cell activation, MagT1 channels were shown to mediate Mg2⫹ influx upon T-cell receptor activation and EGF stimulation (311). In these T cells, Mg2⫹ activates phospholipase C-␥ (PLC␥1), resulting in reduced phosphorylation of protein kinase C (PKC) and inositol trisphosphate (IP3) generation downstream, eventually leading to reduced Ca2⫹ influx (FIGURE 1). In contrast, other reports suggest that PLC␥ activation precedes Mg2⫹ influx (240, 241). The proposition of Mg2⫹ as a dynamic second messenger raises many questions. How do MagT1 or other Mg2⫹ transporters facilitate rapid Mg2⫹ influx when the intracellular and extracellular Mg2⫹ concentrations are almost equal? What mechanism is involved in managing Mg2⫹ after the initial influx, given the absence of Mg2⫹ pumps and major Mg2⫹ binding proteins? Follow-up studies demonstrated that MagT1-deficient cells have severely reduced basal intracellular Mg2⫹ concentrations (79). These results suggest that the effects seen on PLC␥1 are dependent on general intracellular Mg2⫹ availability and further question the physiological role of variable fluxes that are proposed in the second messenger theory. Studying Mg2⫹ dynamics within the cell using fluorescent probes may help to draw definitive conclusions on this matter.

cells showed that applying insulin induced 20% higher intracellular Mg2⫹ concentrations after 16 h (445). Later studies with EGF using the fluorescent probe mag-fura 2 showed an impressive fourfold increase of intracellular Mg2⫹ from 0.3 to 1.4 mM after 20 min of epidermal growth factor (EGF) stimulation (199). The authors state that a rise in Mg2⫹ precedes DNA synthesis, but coincides with and thus may contribute to increases in protein synthesis. Recent studies identifying the molecular mediators of Mg2⫹-dependent cell proliferation have resulted in the membrane, magnesium, mitosis (MMM) model (432). The MMM model proposes that, upon growth factor binding, Mg2⫹ enters the cell or is released from phospholipids in the cell membranes (FIGURE 1). Increased cytosolic Mg2⫹ levels contribute to ribosomal activity and protein synthesis, eventually leading to DNA replication and mitosis. The mammalian target of rapamycin (mTOR) complex is a critical component of the MMM model, as it is the master regulator of cell cycle progression and proliferation (551). Growth factors binding to their receptors leads to phosphoinositide 3-kinase (PI3K) phosphorylation, which activates the mTOR complex (431, 548). Activation of mTOR is MgATP2⫺ dependent, and ATP has been suggested as the main regulator of mTOR activity. However, ATP levels do not change upon growth factor stimulation, whereas Mg2⫹ levels do (445, 537). Therefore, the MMM model proposes Mg2⫹ as the primary regulator of mTOR dynamics and cell proliferation.


DE BAAIJ ET AL. tigated and, therefore, the exact role of Mg2⫹ in enzymatic regulation in cancer remains speculative. In contrast to the proliferative phase of tumor growth, in which tumor cells have high intracellular Mg2⫹ concentrations, low intracellular Mg2⫹ concentrations are associated with increased rates of carcinogenesis and metastasis (74). Low Mg2⫹ conditions and impaired activity of DNA repair mechanisms reduces DNA protection against oxidative stress. Indeed, low dietary Mg2⫹ intake has been associated with the risk of several types of cancers. Epidemiological studies have established a correlation between low Mg2⫹ intake and colon cancer risk (160, 302, 534). In addition, in a study with 1,200 lung cancer patients and a similar number of controls, low dietary Mg2⫹ intake was associated with reduced lung cancer risk (326). However, these results could not be reproduced in other patient cohorts (325, 502).

III. REGULATION OF MAGNESIUM HOMEOSTASIS

A. Magnesium in Intestine Given a daily Mg2⫹ intake of 370 mg, ⬃30 –50% is absorbed in the intestine, resulting in a net uptake of ⫾100 mg. However, if Mg2⫹ intake is low, early reports suggest that up to 80% of dietary Mg2⫹ can be absorbed (189). Mg2⫹ absorption in the gut depends on two separate pathways; paracellular transport is responsible for bulk Mg2⫹ absorption and takes place mostly in the small intestine, whereas fine-tuning occurs in the cecum and colon via transcellular transport (FIGURE 3). In spite of this, the intestine seems to have a limited role in regulation of the Mg2⫹ balance. In contrast to other minerals, intestinal Mg2⫹ absorption is poorly regulated and depends mainly on Mg2⫹ intake (216, 461). Thus the kidneys presumably primarily regulate the maintainance of Mg2⫹ homeostasis. Downloaded from on December 26, 2014

Mg2⫹ serum concentrations range between 0.7 and 1.1 mM in healthy people (323). To maintain constant plasma Mg2⫹ levels, the United States Food and Nutrition Board recommends a daily Mg2⫹ intake of 420 mg for men and

320 mg for women (1). Mg2⫹ homeostasis depends on the collaborative actions of the intestine, responsible for Mg2⫹ uptake from food, the bone, which stores Mg2⫹ in its hydroxy-apatite form, and the kidneys, regulating urinary Mg2⫹ excretion (FIGURE 2).

1. Small intestine Mg2⫹ absorption in the small intestine is hypothesized to be exclusively of a paracellular nature, since Mg2⫹ absorption

FIGURE 2. Magnesium homeostasis. Panels represent the daily amount of Mg2⫹ intake and excretion. Daily the intestines absorb ⬃120 mg and secrete 20 mg of Mg2⫹, resulting in a net absorption of 100 mg. In the kidney daily ⬃2,400 mg Mg2⫹ is filtered by the glomerulus, of which 2,300 mg is reabsorbed along the kidney tubule. This results in a net excretion of 100 mg, which matches the intestinal absorption. Bone and muscle provide the most important Mg2⫹ stores.

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in this region of the intestine correlates linearly to luminal Mg2⫹ concentrations (273, 409). Moreover, the epithelial Mg2⫹ channel TRPM6 is not expressed in the small intestine (196). Mg2⫹ is poorly absorbed in the duodenum, where unfavorable electrochemical gradients may even result in a limited amount of paracellular Mg2⫹ excretion (389). In more distal parts of the small intestine, such as late jejunum and ileum, the driving force for passive Mg2⫹ transport is established by the high luminal Mg2⫹ concentration and the lumen-positive transepithelial voltage of ⬃15 mV (164). The Km for Mg2⫹ transport in the distal small intestine has been reported to be in the range of 4 –12 mM (343, 461). These results suggest that NaCl and water absorption are prerequisites for Mg2⫹ uptake, since water absorption concentrates luminal Mg2⫹. Tight junction permeability underlying paracellular Mg2⫹ transport is still

8

poorly understood. The small intestine is described as the most ion-permeable part of the intestine because of the relatively low expression of “tightening” claudins 1, 3, 4, 5, and 8 (20, 301). Claudins 16 and 19, which are linked to Mg2⫹ transport, are not expressed in the intestine (20, 246). The exact composition of the tight junction complex facilitating intestinal Mg2⫹ absorption remains to be elucidated. 2. Large intestine Mg2⫹ absorption in cecum and colon is thought to be transcellular of nature and is mediated by TRPM6 and TRPM7 on the luminal side of the enterocyte (FIGURE 3). Intestinal expression of TRPM6 is located in cecum and colon (196, 300). In a study with rat colon epithelium, 37% of Mg2⫹ was transported transcellularly (272). This suggests signif-

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FIGURE 3. Magnesium absorption in the intestine. Bulk Mg2⫹ is absorbed paracellular by the late part of the small intestine. Fine-tuning of Mg2⫹ absorption takes place transcellular by the colon, where TRPM6 and TRPM7 Mg2⫹ channels facilitate luminal Mg2⫹ uptake in the enterocyte. CNNM4 provides the basolateral Mg2⫹ extrusion mechanism. TRPM6, transient receptor potential melastatin type 6; TRPM7, transient receptor potential melastatin type 7; ENaC, epithelial sodium channel; CNNM4, cyclin M4.


DE BAAIJ ET AL. icant paracellular transport of Mg2⫹ in the colon, which would be unlikely given the expression of tightening claudins 3, 4, and 8 in this segment (301). In contrast to Ca2⫹, Mg2⫹ transport in colon is independent of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] signaling, nor is TRPM6 expression dependent on 1,25(OH)2D3 (196, 272). It has been suggested that the basolateral Mg2⫹ extrusion mechanism of the enterocyte is coupled to the Na⫹ gradient (424). Indeed, the results of a recent study using CNNM4 KO mice suggest that CNNM4 may act as a Na⫹/Mg2⫹ exchanger at the basolateral membrane of enterocytes (575). CNNM4 KO mice suffer from hypomagnesemia, and functional analysis using Magnesium Green showed that CNNM4 overexpression increased Mg2⫹ efflux in HEK293 cells. However, patients with CNNM4 mutations do not suffer from hypomagnesemia (387, 402).

B. Magnesium in Bone

C. Magnesium in Kidney Approximately 2,400 mg of Mg2⫹ is filtered by the glomeruli on a daily basis. The nephron recovers 95–99% of this; the remaining 100 mg leaves the body via the urine (FIGURE 2). 1. Proximal tubule The mechanisms of proximal tubule (PT) Mg2⫹ reabsorption are poorly understood, but early micropuncture studies showed that ⬃10 –25% of Mg2⫹ is reabsorbed by the proximal convoluted tubule segment of the nephron (304, 411). In the glomeruli, 70% of the serum Mg2⫹ is freely filterable, suggesting that the concentration in the glomerular filtrates and thus at the start of the PT ranges between 0.5– 0.7 mM. The transepithelial potential difference ranges from slightly lumen negative (⫺6 mV) in the early parts of the PT to positive (3 mV) in later parts (287). Micropuncture studies have shown that a 1.9 ratio between the concentrations of Mg2⫹ in the tubular fluid and the interstitial fluid is necessary to initiate Mg2⫹ transport (304). This finding could be explained by the poor tight junction permeability for Mg2⫹ in PT. As a result, water uptake via aquaporin 1 (AQP1) precedes Mg2⫹ reabsorption (410) (FIGURE 5). Consequently, Mg2⫹ reabsorption mainly occurs in the late parts of the PT, where the transepithelial chemical Mg2⫹ gradient is sufficient to favor Mg2⫹ transport. PT Mg2⫹ reabsorption is generally considered to be a passive paracellular process, but there might be some transcellular Mg2⫹ transport via a poorly characterized amiloride-sensitive mechanism (254). In both cases, sufficient Na⫹ transport is required to drive water transport that is a prerequisite for Mg2⫹ reabsorption. Hormonal effects on Na⫹ reabsorption in the PT will therefore also affect Mg2⫹ reabsorption in this segment. However, disturbances of proximal tubular

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Approximately 50 – 60% of the total body Mg2⫹ content is stored in bone. Serum Mg2⫹ concentrations are closely related to bone metabolism; bone surface Mg2⫹ is continuously exchanged with blood Mg2⫹ (14). In bone, Mg2⫹ ions bind at the surface of the hydroxyapatite crystals. Mg2⫹ increases the solubility of Pi and Ca2⫹ hydroxyapatite and thereby acts on the crystal size and formation (443). Mg2⫹ induces osteoblast proliferation; therefore, Mg2⫹ deficiency results in decreased bone formation (320) (FIGURE 4) Mg2⫹deficient rats have reduced osteoblast numbers and decreased bone mass (434). Additionally, Mg2⫹ deficiency increases the secretion of proinflammatory cytokines such as tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, and substance P (434, 552), all of which have been implicated in increased osteoclastic bone resorption (280). These effects may be further enhanced by reduced parathyroid hormone (PTH) and 1,25(OH)2D3 levels, which are often associated with hypomagnesemia (435). Interestingly, Mg2⫹-deficient rats have reduced chondrocyte column formation, which is associated with reduced SRY (sex determining region Y)box 9 (SOX9) expression (200) (FIGURE 4). SOX9 is a key transcription factor in chondrogenesis. In a recent gene ex-

pression study in the Mg2⫹-transporting segment of the kidney, SOX9 mRNA was the most increased in the lowMg2⫹ diet group (104). These findings suggest that SOX9 is an important transcription factor for bone and kidney Mg2⫹ homeostasis.

FIGURE 4. Magnesium storage in bone. Mg2⫹ stimulates osteoblast proliferation in bone and inhibits the release of proinflammatory molecules such as IL-1␤, TNF-␣, and SP, which stimulate osteoclast activity. In bone development, Mg2⫹ stimulates chondrocyte column formation. IL-1␤, interleukin-1␤; TNF-␣, tumor necrosis factor-␣; SP, substance P.

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FIGURE 5. Magnesium reabsorption in the kidney. The glomerulus filters the blood, and along the nephron 95% is reabsorbed. In the late proximal tubule (PT), Na⫹ and H2O reabsorption via NHE3 and AQP1 are prerequisites for paracellular Mg2⫹ transport. Approximately 10 –25% of Mg2⫹ is reabsorbed in the proximal tubule. Bulk Mg2⫹ reabsorption (50 –70%) takes place in the thick ascending limb of Henle’s Loop (TAL). In TAL, Mg2⫹ reabsorption take place paracellular and depends on the uptake of Na⫹ and K⫹ via NKCC2. Fine-tuning (10%) of Mg2⫹ transport takes place transcellular in the distal convoluted tubule (DCT). In DCT, TRPM6 facilitates Mg2⫹ uptake from the pro-urine, which depends on the voltage gradient set by backleak of K⫹ via ROMK and Kv1.1 potassium channels. At the basolateral membrane, Mg2⫹ is extruded via an unknown mechanism, which may be regulated by CNNM2 acting as Mg2⫹ sensor. Mg2⫹ extrusion depends on the Na⫹ gradient, set by the Na⫹-K⫹-ATPase. The activity of the Na⫹-K⫹-ATPase is in turn dependent on K⫹ recycling via Kir4.1. FXYD2 transcription encoding the ␥-subunit of the Na⫹-K⫹-ATPase is regulated by HNF1␤ and PCBD1. Regulation of Mg2⫹ transport in DCT depends on EGF and insulin. Upon activation of the EGFR and IR, an intracellular signaling cascade including PI3K, Akt, and Rac1 results in an increased TRPM6 membrane expression and increased channel activity. Additionally, estrogens have been shown to increase TRPM6 expression. PT, proximal tubule; TAL, thick ascending limb of Henle’s loop; DCT, distal convoluted tubule; CNT, connecting tubule; CD, collecting duct; NHE3, Na⫹-H⫹ exchanger type 3; AQP1, aquaporin 1; NKCC2, Na⫹-K⫹-2Cl⫺ cotransporter; ROMK, renal outer medulla K⫹ channel; ClC-Kb, chloride channel Kb; Kv1.1, voltage-gated K⫹ channel 1.1; TRPM6, transient receptor potential melastatin type 6; NCC, Na⫹-Cl⫺ cotransporter; CNNM2, cyclin M2; FXYD2, FXYD-domain containing 2; HNF1␤, hepatocyte nuclear factor 1␤; PCBD1, pterin-4 alpha-carbinolamine dehydratase 1; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; IR, insulin receptor; PI3K, phosphoinositide 3-kinase; Rac1, Ras-related C3 botulinum toxin substrate 1; Cdk5, cyclin-dependent kinase 5.

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DE BAAIJ ET AL. Mg2⫹ reabsorption generally do not result in clinical symptoms, since more distal segments will compensate for reduced Mg2⫹ uptake in PT. 2. Thick ascending limb of Henle’s loop

The reabsorption of Mg2⫹ in the TAL follows the paracellular pathway and therefore depends on the tight junction permeability (FIGURE 5). Tight junctions form a physical and chemical barrier between the epithelial cells. Their major components are proteins of the claudin family. Currently, 26 claudins have been described in humans (209). Tight junction permeability is determined by the individual claudins in each tight junction complex. TAL tubuli are known to express claudins 3, 10, 11, 14, 16, and 19. Claudins 16 and 19 are considered to be the main claudins influencing Mg2⫹ permeability, since mutations in these proteins result in renal Mg2⫹ wasting (293) (FIGURE 5). However, the role of claudin 16 in Mg2⫹ reabsorption is controversial. Claudin 16 was initially considered to act as a paracellular Mg2⫹ channel, but this hypothesis has not been unequivocally confirmed (207, 245). Reports using the claudin 16 knockdown (KD) mouse model and the LLCPK1 cell model suggest that claudin 16 increases Na⫹ permeability (227, 245, 466). This would imply that claudin 16 is mainly involved in the regulation of the transepithelial voltage gradient by controlling the paracellular Na⫹ backleak. In MDCK-C7 cells overexpressing claudin 16, Na⫹ permeability yet remained stable, whereas Mg2⫹ permeability increased significantly (207). Claudin 16 KD mice demonstrate a twofold lower permeability ratio for Na⫹ over Cl⫺ without a change in paracellular conductance. Consequently, the transepithelial voltage collapsed, reducing the driving force for Mg2⫹ reabsorption in TAL (466). Claudin 19 has been studied less extensively, but has been suggested to increase the tight junction barrier function (24). The claudin 19 KD mouse exhibits highly increased

Claudin 14 reduces the cation specificity of tight junction barriers, when coexpressed with claudin 16, or with claudin 16-claudin 19 complexes (180). Consequently, claudin 14 KO mice exhibit increased serum Mg2⫹ values and decreased urinary Mg2⫹ excretion. This agrees with previous findings in MDCK cells showing that claudin 14 acts as a nonspecific cation blocker (45, 560). Studies on claudin 14 KO mice have mainly focused on Ca2⫹ homeostasis, since claudin 14 expression is highly Ca2⫹ sensitive (121, 180). The CaSR regulates claudin 14 expression and Ca2⫹ reabsorption in the TAL by downregulation of two microRNAs, miR-9 and miR-374. Since CaSR is also activated by Mg2⫹, although to a lesser extent than Ca2⫹, it would be interesting to address the effect of elevated serum Mg2⫹ levels on claudin 14 expression in future studies. Recently, claudin 10 has been identified as an important factor in cation selectivity in TAL, as demonstrated in a mouse model where claudin 10 was deleted specifically in this segment (57). Claudin 10 TAL-KO mice show hypermagnesemia, nephrocalcinosis, and impaired paracellular Na⫹ permeability. In the absence of claudin 10, TAL tight junctions became more permeable to Ca2⫹ and Mg2⫹ and the transepithelial voltage increased. These results are in line with in vitro studies overexpressing claudin 10b, suggesting that this splice variant is mainly expressed in TAL (57, 208). 3. Distal convoluted tubule The distal convoluted tubule (DCT) determines the final urinary Mg2⫹ concentration, since no reabsorption of Mg2⫹ takes place beyond this segment. Approximately 10% of the total Mg2⫹ is reabsorbed by tightly regulated transcellular transport mechanisms (64). DCT cells form a high-resistance epithelium with a lumen-negative voltage of approximately ⫺5 mV (192, 571). In DCT, TRPM6 divalent cation channels mediate luminal Mg2⫹ uptake (234, 235) (FIGURE 5). Within the kidney, TRPM6 is specifically expressed in DCT, and its activity is regulated by intracellular Mg2⫹ (540). TRPM6 contains six transmembrane spanning domains with a pore region between the fifth and sixth segment and a large kinase domain fused to the channel’s intracellular COOH terminus. TRPM6 may function in homo- and heteromeric tetramers with TRPM7, al-

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Whereas most electrolytes are majorly transported in the PT, the thick ascending limb of Henle’s loop (TAL) is the main location for Mg2⫹ reabsorption (236, 299, 420). Due to the unique properaties of this segment, ⬃50 –70% of filtered Mg2⫹ is reabsorbed here. Most of the Mg2⫹ is reabsorbed by the cortical part of the TAL, since medullary Mg2⫹ reabsorption is negligible (468). Paracellular bulk Mg2⫹ transport is dependent on the lumen-positive transepithelial voltage (⫹10 mV) that is determined by the activity of the Na⫹-K⫹-2Cl⫺ cotransporter (NKCC2) and the subsequent secretion of K⫹ at the apical membrane (192). Inhibition of NKCC2 by furosemide diuretics therefore decreases TAL Mg2⫹ reabsorption (see sect. VB3). Further contributors to the transepithelial membrane voltage are K⫹ secretion via renal outer medullary potassium channel (ROMK) and paracellular backflux of Na⫹ ions as a result of decreasing luminal Na⫹ concentrations (329).

urinary excretion of K⫹, Mg2⫹, and Ca2⫹, but Mg2⫹ is the only electrolyte altered at the serum level (246). The discrepancy between studies with claudin 16 and claudin 19 isoforms might be explained by their interdependence in forming functional tight junction barriers (246, 247). Both in vitro and in vivo studies demonstrated that claudins 16 and 19 need to interact for proper insertion in the tight junction to become functionally active. Further differences in experimental results may depend on the endogenous expression of other claudin isoforms in the specific cell types used in these experiments.


MAGNESIUM IN MAN though there is some controversy about the necessity of TRPM7 for TRPM6 function (314, 588).

A chemical gradient for Mg2⫹ entry in DCT cells is almost absent. The luminal Mg2⫹ concentrations vary between 0.2 and 0.7 mM, and the intracellular Mg2⫹ levels are typically in the range of 0.5–1 mM. Therefore, luminal Mg2⫹ entry is purely dependent on the negative membrane potential in the DCT cell. Luminal K⫹ channels are indispensable for maintaining the necessary driving force for Mg2⫹ uptake. The voltage-gated K⫹ channel Kv1.1 has been suggested to provide efflux K⫹ currents resulting in hyperpolarization of the luminal membrane, although expression levels in the DCT are limited (104, 176). To prevent Mg2⫹ overload and hyperpolarization of the luminal membrane, intracellular Mg2⫹ blocks Kv1.1 (179). Interestingly, recent studies suggest that other potassium channels in the luminal membrane of DCT cells may have comparable roles. ROMK is prominently expressed in DCT, and its expression in this segment is regulated by dietary Mg2⫹ (104, 572). Similar to Kv1.1, intracellular Mg2⫹ blocks ROMK currents, suggesting a regulatory function on Mg2⫹ homeostasis (578). Moreover, indirect inhibition of ROMK by aldosterone or eptihelial Na⫹ channel (ENaC) blockers represent the only effective approach to prevent renal Mg2⫹ wasting in most clinical situations (140). Several proteins have been proposed to mediate Mg2⫹ extrusion to the bloodstream, but general consensus of the extrusion mechanism has not been reached (424). Due to

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Recently mutations in the SLC41A1 Mg2⫹ transporter were described to cause a nephronophthisis-like phenotype (251). Immunohistological studies showed expression in DCT, but the stainings were not conclusive about the subcellular localization (apical or basolateral) of SLC41A1 proteins (251). By the use of Mag-Fura, SLC41A1 was demonstrated to increase both Mg2⫹ absorption and Mg2⫹ extrusion (251, 289). These results suggest that SLC41A1 plays a role in DCT Mg2⫹ reabsorption, although further studies are necessary to elucidate the mechanisms by which SLC41A1 mediates Mg2⫹ transport. Parvalbumin is exclusively expressed in DCT within the kidney, where it may function as a Ca2⫹/Mg2⫹ buffer (456). Although parvalbumin has much higher affinity for Ca2⫹ than for Mg2⫹ (dissociation constants are ⬃5–10 nM for Ca2⫹ and ⬃30 ␮M for Mg2⫹), the cation binding sites of parvalbumin will be mainly occupied by Mg2⫹ (377). This can be explained by the fact that the intracellular concentration of Mg2⫹ (0.5–1 mM) vastly exceeds that of Ca2⫹ (50 –100 nM). In mouse and human kidney, parvalbumin is exclusively expressed in the early DCT (44). In late DCT and CNT, calbindin-D28K is the main Ca2⫹-binding protein. The exact role of parvalbumin in DCT remains to be investigated. Parvalbumin KO mice do not have altered serum or urine Mg2⫹ levels under basal conditions; these mice have reduced NCC expression, but display normal tubule morphology (44). DCT parvalbumin expression is highly sensitive to dietary Mg2⫹ availability, suggesting an important role for parvalbumin in Mg2⫹ reabsorption in DCT (104).

IV. MAGNESIUM IN PHYSIOLOGY AND PATHOPHYSIOLOGY The human body contains ⬃24g Mg2⫹, of which 99% is stored in bone, muscle, and other soft tissues. Mg2⫹ is crit-

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TRPM6 is regulated by numerous factors at the level of transcription, plasma membrane availability, and activity (69). EGF and insulin act on TRPM6 by a PI3K-Akt-Rac1 dependent mechanism, increasing the insertion of TRPM6 in the membrane (361, 515) (FIGURE 5). Insulin may directly affect TRPM6 activity through cylin-dependent kinase 5 (cdk5)-dependent phosphorylation of the channel. Patients with reduced EGFR or insulin receptor (IR) activity are therefore more susceptible to hypomagnesemia (361, 459). Additionally, estrogens increase TRPM6 mRNA expression (196). Over the last decade, several important interactors of TRPM6, including receptor for activated C-kinase 1 (RACK1) and prohibitin2 (PHB2/REA), have been identified (70, 71). RACK1 interacts with the a-kinase domain of TRPM6 in the autophosphorylated state, thereby reducing TRPM6 activity (70). Other modulators of TRPM6 activity include dietary Mg2⫹, pH, and ATP (516). Interestingly, acidification-induced current potentiation is dependent on residues p.Glu1024 and p.Glu1029, which also determine the pore selectivity for Mg2⫹ (313, 367). Moreover, recent findings indicate that TRPM6 is inhibited by low concentrations of intracellular ATP (IC50 29 ␮M), questioning the physiological activity of monomeric TRPM6 channels (588). Extracellular ATP also inhibits TRPM6 activity via the purinergic receptor P2X4 (103).

the absence of a representative DCT cell model, the properties of Mg2⫹ extrusion have not been elucidated. Nevertheless, over the last decade several groups claimed to have identified Mg2⫹ extrusion proteins. Originally described in 2002, cyclin M2 (CNNM2, previously known as ACDP2) is exclusively expressed at the basolateral membrane of DCT and CNT cells within the kidney (105, 497, 545). Moreover, expression of CNNM2 is sensitive to dietary Mg2⫹ availability (104, 497). CNNM2 was initially depicted as Mg2⫹ transporter, since overexpression in Xenopus laevis oocytes allows uptake of a variety of divalent cations, with highest affinity for Mg2⫹ (184). However, these results could not be confirmed in mammalian cell lines (497). Alternatively, a Mg2⫹-sensing function has been proposed, since CNNM2 harbors a Mg-ATP binding site in its cystathionine-␤-synthase (CBS) domains (105). CNNM2 increases Mg2⫹ uptake in HEK293 cells (28). Nevertheless, it remains unclear whether CNNM2 mediates Mg2⫹ uptake directly or activates other Mg2⫹ carriers.


DE BAAIJ ET AL. ical to the function of basically every organ in the human body. Moreover, Mg2⫹ deficiency is associated with a wide range of diseases, and as a result Mg2⫹ supplementation is considered as potential treatment in many of them (TABLE 2). This part of the review focuses on the organ-specific functions of Mg2⫹ and provides an overview of all major diseases in which Mg2⫹ may play a role.

A. Magnesium in Brain

In the adult brain, this process is further amplified by the action of inhibitory ␥-aminobutyric acid (GABA) receptors, whose function is also regulated by Mg2⫹. GABAA receptors are ionotropic anion channels that open upon GABA binding and facilitate Cl⫺ influx (250). Since the equilibrium potential of Cl⫺ is 10 –20 mV lower than the membrane potential, this influx contributes to hyperpolarization of the neuronal cells. Extracellular Mg2⫹ stimulates GABAA receptors resulting in hyperpolarized neuronal cells (353). When Mg2⫹ concentrations in the central nervous system (CNS) are low, GABAA receptors are less stimulated. Consequently, the membrane potential will be higher,

Table 2. Therapeutic use of Mg2⫹ Disease

Cochrane Review

Large-Scale Clinical Studies

Guidelines

First drug of choice Preeclampsia Arrhythmia–Torsades des Pointes

RR: 0.41, 95% CI: 0.29–0.58 (130)

(223) (591)

Alternative drug of choice Migraine Asthma Super-refractory status epilepticus Muscle cramps

RR: 0.53, 95% CI: 0.05–5.31 (404)

Magnetic

No. cramps: ⫺3.93%, 95% CI: ⫺21.12 to 13.26% (168)

(237) (3) (476) (274)

Experimental Stroke Subarachnoid hemorrhage Myocardial infarction

RR: 0.75, 95% CI: 0.57–1.00* (125) OR: 0.59, 95% CI: 0.49–0.70⫹ (312)

Hypertension Traumatic brain injury

DBP: ⫺2.2 mmHg, 95% CI: ⫺3.4 to ⫺0.9 (119) GS: 0.02, 95% CI: ⫺0.38 to 0.041 (25)

FAST-MAG Images IMASH MASH-II LIMIT-2 ISIS-4

This table summarizes all diseases in which Mg2⫹ has been considered as treatment by the official American guidelines. Moreover, it lists all large-scale clinical studies and meta-analyses of small-scale clinical studies by the Cochrane collaboration. RR, risk ratio; OR, odds ratio; CI, confidence interval; DBP, diastolic blood pressure; GS, Glasgow score. Reference numbers are given in parentheses. *In addition to standard nimodipine treatment. ⫹Early mortality in patients treated with ⬍75 mmol of magnesium compared with placebo groups.

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Low serum Mg2⫹ values are associated with a wide range of neurological diseases such as migraine, depression, and epilepsy. Neuronal Mg2⫹ concentrations are of major importance in the regulation of N-methyl-D-aspartate (NMDA) receptor excitability. NMDA receptors are essential for excitatory synaptic transmission, neuronal plasticity, and excitotoxicity and therefore play an important role in developmental plasticity, learning, and memory (384). NMDA receptors are activated upon glutamate binding and mediate the influx of Ca2⫹ and Na⫹ ions and the efflux of K⫹ ions. Every NMDA receptor consists of four subunits, each with different biochemical properties (97). In Mg2⫹ deficiency, NMDA receptors become hyperexcitable, which can be explained by inhibitory function of extracellular Mg2⫹ on the receptors (335, 372) (FIGURE 6). Glutamate from the presynaptic neuron will bind both the ionotropic 2-amino-3(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA)

and NMDA receptors on the postsynaptic neuron. At a normal membrane potential of ⫺70 mV, Mg2⫹ ions block NMDA receptors. Therefore, only AMPA receptors will be activated and consequently facilitate an influx of cations. Only when the membrane potential rises above ⫺60 mV the Mg2⫹ block is relieved and NMDA receptors are opened upon glutamate binding. The unlocking mechanism consists of a slow and a fast component, which depend on the relative expression of subunits that compose the channel (87, 536). Upon reduced extracellular Mg2⫹ concentrations, less NMDA channels will be blocked, and more NMDA channels can be opened at relatively low membrane potentials (351). This increased excitatory postsynaptic potential causes hyperexcitability of the neurons.


MAGNESIUM IN MAN

which in turn relieves the Mg2⫹ block of the NMDA receptor and contributes to hyperexcitability of the neurons. The final mechanism contributing to the hyperexcitability of NMDA-receptor rich neurons is inhibiting glutamate release from the presynaptic neuron. Release of glutamate can be inhibited by high extracellular Mg2⫹ concentrations (257, 318, 486). Although the exact mechanism by which Mg2⫹ reduces glutamate release is still unknown, it could be related to the inhibition of voltage-gated Ca2⫹ channels, as glutamate release is triggered by an influx of Ca2⫹ after an action potential (364). As a result of the described mechanisms, low extracellular Mg2⫹ levels in the CNS contribute to the hyperexcitability

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of NDMA receptor. The excessive intracellular Ca2⫹ in the neurons may lead to the production of toxic reactive oxygen species (ROS) and eventually to neuronal cell death. In addition to increasing the hyperexcitability of excitatory neuronal pathways, Mg2⫹ has an important role in the regulation of oxidative stress and the release of neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P. CGRP is secreted from sensory neurons and has a vasodilatory effect (48). Mg2⫹ may increase CGRP expression and secretion, as has been shown in women with preeclampsia (26, 151), although an opposite effect was reported in women with Raynaud’s phenomenon (359). Mg2⫹ deficiency increases the release of substance P, which is a neuorinflammatory tachykinin (554), stimulating the

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FIGURE 6. Magnesium in brain. Mg2⫹ is an important regulator of glutamate signaling in the brain. Upon glutamate release, glutamate binds NMDAR and AMPAR in the postsynaptic neuron. Mg2⫹ blocks the NMDAR at membrane potentials less than ⫺60 mV. Therefore, AMPAR needs to depolarize the cell membrane before NMDAR will be activated. Moreover, Mg2⫹ stimulates GABAAR and thereby strongly influences the membrane potential of the postsynaptic neuron. In the presynpatic neuron, Mg2⫹ inhibits glutamate release by antagonizing calcium. Moreover, Mg2⫹ increases the expression and secretion of CGRP and inhibits the production of NO and the release of SP. Inset: current-voltage curve of NMDAR current. Mg2⫹ blocks the NMDAR receptor at voltages lower than ⫺60 mV. NMDAR, N-methyl-D-aspartate receptor; AMPAR, ␣-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptor; GABAAR, ␥-aminobutyric acid receptor; CGRP, calcitonin gene-related peptide; NO, nitric oxide; SP, substance P; IL-1␤, interleukin-1␤; TNF-␣, tumor necrosis factor-␣.


DE BAAIJ ET AL. secretion of inflammatory mediators such as IL-1, -2, -4, -5, -10, -12, and -13 as well as TNF-␣ (552, 554). Moreover, Mg2⫹ enhances the activity of nitric oxide synthases (NOS) through a NMDA receptor-dependent mechanism (80, 392). Nitric oxide (NO) has multiple functions in the brain including vasodilation, regulation of gene transcription, channel activity, and neurotransmitter release (493). Altogether, the role of Mg2⫹ in the regulation of neuropeptide release may have serious consequences in neuronal disease. 1. Migraine

The first reports of Mg2⫹ treatment for migraine patients appeared in the 1960s and 1970s (542), and since then the pharmacological role of Mg2⫹ has been slowly recognized. Although presently the effectiveness of Mg2⫹ treatment for the majority of patients is still debated (334, 386), Mg2⫹ is a second line drug for migraine patients (148, 237). Over the last decades several double-blind placebo-controlled randomized trials have provided evidence for a beneficial effect of oral Mg2⫹ supplementation on the number of migraine attacks (294, 393, 507) as well as the intensity of the pain during these attacks (149, 294). One clinical trial failed to show any favorable effect (397), but patients in this study suffered from diarrhea. Although Mg2⫹ is generally well tolerated, supplementation with certain Mg2⫹ salts often results in diarrhea and malabsorption of the Mg2⫹. Intravenous Mg2⫹ supplementation in acute migraine and cluster headache treatment provided pain relief in several cases (47, 112, 332, 333). In contrast, other studies failed to demonstrate such an effect (78). A recent meta-analysis combining five studies on the effect of intravenous Mg2⫹ administration on migraine did not show significant improvements on pain relief [Risk ratio (RR): ⫺0.07, 95% confidence interval (CI): ⫺0.23 to 0.09]. However, the relatively low number of patients included (n ⫽ 295) is one of the major limits of this analysis (86). Efficacy of Mg2⫹ treatment in combination with other drugs is doubtful; Mg2⫹ combined with metoclopramide and riboflavin did not demonstrate any efficacy in treating migraine (94, 328).

In 1921, Weston (557) reported the beneficial role of Mg2⫹ in treatment of patients with depression. Nevertheless, large-scale, placebo-controlled double blind clinical trials assessing the efficacy of Mg2⫹ supplementation on depression are still lacking. Studies examining the association between serum Mg2⫹ concentrations and depression severity are not conclusive; some studies report altered blood Mg2⫹ levels, while others do not find differences (reviewed in Ref. 114). Since serum Mg2⫹ levels do not necessarily reflect neuronal Mg2⫹ availability, determining Mg2⫹ levels in CSF may be more relevant for patients with depression. Only three cross-sectional studies have addressed this issue, and none of them found altered CSF Mg2⫹ concentrations in depressed patients compared with healthy controls (35, 171, 310). Despite this, several investigations have proposed that Mg2⫹ may relieve depression by blocking the NMDA receptor, whose dysfunction is a major causative factor in depression pathology (135, 143, 400, 557). To date, two interventional studies have investigated the role of Mg2⫹ in treating depression and their results are contradictory. In a randomized trial examining depressed elderly patients with diabetes mellitus type 2 and hypomagnesemia, Mg2⫹ supplementation was as effective as standard imipramine treatment (37). However, this study lacked a placebo control group. Moreover, it should be noted that imipramine therapy is nowadays largely replaced by selective serotonin reuptake inhibitors (SSRI). Another limit of the studies is the small sample population (23 patients). Therefore, large-scale studies are necessary to delineate a role of Mg2⫹ in the treatment and prevention of depression. 3. Epilepsy Seizures are often associated with genetic and acquired forms of hypomagnesemia (see sect. V). Many studies have found that patients suffering from epilepsy display lower blood Mg2⫹ values (212, 375, 482). The link between Mg2⫹ status and the development of seizures may be explained by the role of Mg2⫹ in NMDA receptor blockade. Most studies addressing this issue show a small but significant decrease in CSF Mg2⫹ levels in epilepsy patients (492). In eclampsia patients, Mg2⫹ has proven to be successful in reducing the risk of recurrent convulsions (198). For other types of seizures, the evidence is less conclusive. In 1933 the first report of Mg2⫹ infusions in eight status epilepticus patients, a life-threatening form of epilepsy in which patients suffer from continuous seizures without regaining consciousness, was successful in all cases (496). However, modern reports of Mg2⫹ infusion treatment of status epilepticus patients have more variable outcomes and are not as conclusive (159, 383). Mg2⫹ infusions are therefore considered a second line of treatment, when anti-epileptic drugs and anesthetics have proven to be unsuccessful. Absence of large-scale randomized double blind placebo-controlled tri-

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Migraine has been linked to low levels of magnesium in serum and cerebrospinal fluid (CSF) (414, 457). Migraine headaches are the consequence of cortical spreading depression (CSD), which consists of an intense membrane depolarization and repolarization in neurons and glial cells (308, 388). CSD can be evoked by NMDA receptor activation (181). Therefore, patients with an increase in neuronal excitability due to low CSF Mg2⫹ levels are more susceptible to migraine attacks. Moreover, patients suffering from migraine are often hypotensive during attacks (462), which can be explained by increased NO levels. NO is an important vasodilator and modulator of brain blood flow (376). As an inhibitor of NO production, reduced Mg2⫹ values may result in decreased NO levels (80, 392).

2. Depression


MAGNESIUM IN MAN als obstructs the implementation of Mg2⫹ as general antiepileptic treatment (9). 4. Stroke

Approximately 5% of all strokes are caused by subarachnoid hemorrhage (SAH) that results from ruptured aneurysms. Delayed cerebral ischemia (DCI) is the major cause of death and disability in patients that survive the first 24 h (126). Interestingly, patients with SAH often present with hypomagnesemia (531, 532). Vasoconstriction is the main cause of DCI, and this may be enhanced when the patient is Mg2⫹ deficient. Over the last decade, several clinical trials have examined the addition of Mg2⫹ administration to the standard nimodipine treatment (358, 533, 555, 568). In

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5. Brain injury Mg2⫹ deficiency is regularly found in patients with traumatic brain injury (TBI) and spinal cord injury (SCI) (81, 268). Reduced CSF Mg2⫹ levels increase oxidative stress (ROS, NO) and lipid peroxidation, which both contribute to the severity of TBI (77, 416). Additionally, it has been proposed that Mg2⫹ deficiency increases the release of substance P in TBI, resulting in neuronal cell death and edema (539). In animal experiments, Mg2⫹ improved sensorimotor/motor function as well as cognitive function (233). In a small study of 30 TBI patients, Mg2⫹ supplementation improved patient outcomes as measured by the Glasgow outcome scale (OR 4.13; 95% CI 1.39 –12.27) (116). A large phase 3 randomized placebo-controlled clinical trial tested the effect of two doses of Mg2⫹ treatment on 6 mo mortality, seizures, functional measures, and neuropsychological tests in 500 TBI patients. Surprisingly, patients receiving Mg2⫹ treatment did significantly perform worse on the primary outcome than control patients (48 vs. 54; 95% CI ⫺10.5 to ⫺2), suggesting an adverse effect of Mg2⫹ (511). A meta-analysis on all clinical trials with TBI patients confirmed that there is no evidence for a neuroprotective role of Mg2⫹ in TBI (25). This demonstrates again the difficulties in translating the results obtained in animal studies to the clinic (111). 6. Parkinson’s disease Parkinson’s disease is characterized by a loss of dopaminergic neurons. Parkinson’s patients have low Mg2⫹ concentrations in cortex, white matter, basal ganglia, and brain stem (580). Interestingly, rats with chronic low Mg2⫹ intake exhibit a significant loss of dopaminergic neurons (381). In vitro experiments often use differentiated PC12 cells and 1-methyl-4-phenylpyridium ion (MPP⫹) to model Parkinson’s disease at the cellular level. In this experimental

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Stroke is one of the major causes of death in the Western society and has been associated with a drop in serum Mg2⫹ levels (19). There may be multiple roles for Mg2⫹ in the etiology of stroke. Low serum Mg2⫹ levels increase NMDA receptor activity and thus more glutamate and Ca2⫹ influx. Excessive Ca2⫹ and glutamate influx via the NMDA receptor may be the basis of excitotoxicity during stroke (137). Since clinical trials with NMDA receptor antagonists have proven to be unsuccessful in treatment of stroke (256), it is, however, unlikely that NMDA receptor blockade alone can fully explain the role of Mg2⫹ in the development and onset of stroke. Mg2⫹ also blocks other voltage-gated Ca2⫹ channels that may be involved in Ca2⫹ cytotoxicity. Additionally, Mg2⫹ has a vasodilatory effect, which may be beneficial for patients suffering from ischemic stroke. Although more than 100 neuroprotective agents were tested in animals, not a single agent has been proven successful in a phase 3 clinical trial (111). After several pilot studies showed beneficial effects of Mg2⫹ on clinical outcome parameters, two large randomized controlled trials have been performed to determine the role of Mg2⫹ administration in stroke treatment (355, 356, 449). The Intravenous Magnesium Efficacy in Stroke Trial (IMAGES) enrolled over 2,500 stroke patients and gave a 16 mmol MgSO4 bolus injection within 12 h of a stroke, followed by a maintenance dose of 65 mmol over 24 h. No beneficial effects were reported on the primary outcome, death and disability at 3 mo [odds ratio (OR) 0.95, 95% CI 0.80 –1.13]. However, in a subgroup of patients treated within the first 3 h (3.3% of the cohort), a favorable death or disability outcome of 0.66 (95% CI 0.25–1.70) was reported (356). Since animal studies indicate that Mg2⫹ treatment is only successful when applied within 3 h of the onset of the stroke (579), a largescale follow-up randomized controlled trial is currently running which aims to treat patients with Mg2⫹ within the first hours after stroke in a prehospital and emergency department setting. Although the trial is still running, first reports indicate that they have succeeded in including 72% of ⬃1,000 patients within the first hour (448). Final results from this FAST-MAG study will help determine the efficiency of Mg2⫹ treatment for stroke patients.

2005, in the Magnesium and Acetylsalicylic acid in Subarachnoid Hemorrhage (MASH-I) study poor outcomes were 23% reduced (RR 0.77; 95% CI 0.54 –1.09) and DCI was reduced by 35% (RR 0.65; 95% CI 0.40 –1.05) (533). However, more recent studies in larger study-cohorts did not report beneficial effects. In the intravenous magnesium sulfate for aneurysmal subarachnoid hemorrhage (IMASH) double-blind randomized placebo-controlled trial, 6 mo favorable outcome was similar between the patients given MgSO4 and the control, 64 and 63%, respectively (RR 1.0; 95% CI 0.7–1.6) (568). Comparable results were obtained more recently, in the MASH-II multicenter randomized placebo-controlled in a cohort of 1,200 patients; 74% had a favorable outcome in the Mg2⫹ group and 75% in the control group (RR 1.03; 95% CI 0.85–1.25) (124). Overall, these studies suggest that intravenous Mg2⫹ treatment does not improve clinical outcome after aneurysmal subarachnoid hemorrhage.


DE BAAIJ ET AL. (FEV) and forced vital capacity (FVC) (60, 174). Lung Mg2⫹ research suffers from a lack of fundamental studies. As a result, the mechanisms that explain the role of Mg2⫹ in lung function are poorly understood, and hypotheses are mainly based on studies in other cell types and organs. Nevertheless, the role of Mg2⫹ in lung function may be explained at three levels: 1) Mg2⫹ has a strong vasodilator and bronchodilator effect; 2) Mg2⫹ regulates the release of acetylcholine (ACh) and histamine; and 3) Mg2⫹ acts as anti-inflammatory agent (FIGURE 7).

7. Other brain pathologies

From studies on coronary artery related diseases, it is known that Mg2⫹ has a vasodilatory effect (512, 513). Like many vasodilators, Mg2⫹ also has a bronchodilating effect (229, 374). Although the mechanisms underlying Mg2⫹induced bronchodilation remain to be elucidated, Mg2⫹ is known to inhibit the release of ACh and histamine, both known to induce bronchoconstriction (88, 291, 398, 427). Moreover, Mg2⫹ may reduce the airway inflammation that underlies several lung diseases, including chronic obstructive pulmonary disorder (COPD) and cystic fibrosis. In line with this, Mg2⫹ deficiency has been reported in children with bronchitis, and low Mg2⫹ levels can induce an inflammatory response in lung allografts (43, 440). Most of our understanding of the role of Mg2⫹ in inflammation comes from studies in brain, heart, and intestine (450, 509, 553), and only a few studies have examined the anti-inflamma-

Low serum Mg2⫹ levels have also been associated with a wide range of neurological pathologies including schizophrenia, bipolar disorder, neuroses, addiction, stress, and Alzheimer’s disease (538). Although this suggests that Mg2⫹ deficiency plays a role in the etiology of these pathologies, all reports to date are of an epidemiological nature. There are currently no reports of clinical trials examining the effect of Mg2⫹ supplementation on the disease outcome of these diseases.

B. Magnesium in Lung Dietary Mg2⫹ intake has been repeatedly associated with lung function, as assessed by forced expiratory volume

FIGURE 7. Magnesium in lung. Mg2⫹ stimulates broncholdilation by inhibiting the release of bronchoconstrictors histamine and actylcholine from mast cells and neurons, respectively. Moreover, it inhibits the vasoconstriction by reducing the release of NO and SP. His, histamine; ACh, acetylcholine; NO, nitric oxide; SP, substance P.

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model, mitochondrial Mg2⫹ concentrations were decreased as was demonstrated using the mitochondrial KMG-301 fluorescent Mg2⫹ probe (475). Moreover, Mg2⫹ transporter SLC41A1 is located on the PARK16 locus that is associated with Parkinson’s disease (576). Recent characterization of the SLC41A1-pA350V single nucleotide polymorphism (SNP) linked to Parkinson’s disease evidenced a gain-of-function effect (290). These studies suggest that Mg2⫹ supplementation may be beneficial for patients suffering from Parkinson’s disease.


MAGNESIUM IN MAN tory function of Mg2⫹ in lung. Nevertheless, it is generally accepted that Mg2⫹ protects against inflammation by reducing oxidative stress, inhibiting substance P release, and preventing Ca2⫹ toxicity by inhibiting voltage-gated Ca2⫹ channels (450, 553). Mg2⫹ also modulates NF␬B activation by influencing lipid peroxidation (17, 153). All together, these characteristics make Mg2⫹ a potential therapeutic agent for lung diseases such as asthma and COPD. 1. Asthma

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Mg2⫹ deficiency has been repeatedly reported in patients with cystic fibrosis (210, 380). Patients with cystic fibrosis are often treated with recombinant human DNase-I to degrade the viscous mucus. However, the recombinant DNase requires Mg2⫹ to function, and efficiency of the treatment depends, therefore, on the Mg2⫹ status of the patient (444). It was suggested that Mg2⫹ treatment in itself would be sufficient to trigger endogenous DNase activity in the sputum (426). To further examine the potential role of Mg2⫹ as treatment for cystic fibrosis patients, a small double-blind, randomized, placebo-controlled crossover study tested the effect of oral Mg2⫹ supplementation on respiratory muscle strength and disease severity (444). Patients supplemented with Mg2⫹ increased their maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP). Although these first results are promising, more large-scale follow-up studies are necessary to assess the effects of Mg2⫹ in cystic fibrosis patients. 3. COPD Serum Mg2⫹ levels have been associated with disease progression in patients with COPD (31, 46). Given the bronchodilating effects of Mg2⫹, several studies have examined whether intravenous or nebulized Mg2⫹ may benefit COPD patients. In 1995, a small study of 27 COPD patients examined the effect of 1.2 g MgSO4 infusion after ␤-agonist administration. Although the sample size was small, Mg2⫹treated patients demonstrated higher peak expiratory flow values compared with placebo-treated patients (22 ⫾ 29 vs. 6 ⫾ 24%) (485). In another small randomized double-blind controlled trial, Mg2⫹ infusion resulted in improved functional respiratory capacity (⫺0.48 l, 95% CI: ⫺0.96, ⫺0.01), inspiratory capacity (0.21 l, 95% CI: 0.04 – 0.37), MIP (10 cmH2O, 95% CI: 1.6 –18.4), and MEP (10.7 cmH2O, 95% CI: 0.20 –21.2) (123). In contrast, a recent study using combined intravenous and nebulized MgSO4 administration in 62 COPD patients did not detect significant effects on the primary outcome, as measured by hospital admission, intubation, and hospital death rates, nor did they find improved lung function (370). A larger recent study testing nebulized MgSO4 did not detect improved lung function after 90 min, as determined by FEV (136). Patients that received 151 mg MgSO4 in addition to standard salbutamol treatment demonstrated similar FEV (⫺0.026 l, 95% CI ⫺0.15 to 0.095). Altogether, the efficacy of Mg2⫹ treatment in COPD remains unclear and may depend on the route of administration and the combination with the use of additional drugs.

C. Magnesium in Heart and Vasculature Mg2⫹ plays an important role in heart function by influencing myocardial metabolism, Ca2⫹ homeostasis, vascular

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Several studies have reported low serum Mg2⫹ levels or low erythrocyte Mg2⫹ levels in asthmatic patients (21, 141, 219). However, others could not detect a Mg2⫹ deficiency in patients with asthma, suggesting that Mg2⫹ levels may depend on the severity of the disease (109, 276). Since Mg2⫹ relaxes smooth muscle cells, low Mg2⫹ levels cause bronchoconstriction and vasoconstriction, resulting in more asthmatic exacerbations (374). Moreover, Mg2⫹ regulates the release of ACh and histamine, which have both been implicated in asthma (170, 371). Interestingly, asthmatic C57/Bl6 mice have lower serum and intracellular Mg2⫹ concentrations than controls, which could be explained by a decreased renal TRPM6 expression (265). In 1940, Victor Haury (221) was the first to treat bronchial asthma patients with Mg2⫹ injections to relieve asthmatic paroxysms. Since then, ⬃25 randomized controlled studies have been published examining the effects of nebulized and intravenous Mg2⫹ administration in asthma patients. A recent systematic review failed to demonstrate significant improvement of respiratory function [standardized mean difference (SMD) 0.17, 95% CI ⫺0.02 to 0.36] or hospital admissions (RR 0.68, 95% CI 0.46 to 1.02) for patients with acute asthma who had been given nebulized Mg2⫹, although both parameters almost reached statistical significance (348). In studies using intravenous Mg2⫹ injection, respiratory function increased slightly in adults, but the most significant improvements were found in children (SMD 1.94, 95% CI 0.80 –3.08), and children’s hospital admissions were reduced (RR 0.70, 95% CI 0.54 – 0.90) (348). A recent systematic review within the Cochrane collaboration addressing nebulized Mg2⫹ for treatment of acute asthma concluded that respiratory function is not significantly improved in Mg2⫹-treated patients compared with patients receiving ␤2-agonists (404). However, the patients covered by this systematic review were mainly adult patients. Recently, the outcomes of the MAGNEsium Trial In Children (MAGNETIC) randomized controlled study were published, showing improvement of the asthma severity score at 60 min (0.25, 95% CI 0.02– 0.48) and 240 min (0.20, 95% CI 0.01– 0.40) after inhalation of MgSO4 (405). The MAGNETIC study was not published at the time of the systematic reviews, and future analysis including this trial may further substantiate the beneficial effects of Mg2⫹ in treatment of children with asthma.

2. Cystic fibrosis


DE BAAIJ ET AL. tone, peripheral vascular resistance, and cardiac output. Mg2⫹ exerts its effects in three ways: 1) Mg2⫹ regulates the activity of ion channels in the cardiac cells, thereby affecting the electrical properties of the myocardium (354); 2) Mg2⫹ regulates myocardial contractility by influencing the intracellular Ca2⫹ mobility; and 3) Mg2⫹ has an anti-inflammatory and vasodilatory effect (FIGURE 8). The cardiac action potential consists of five phases: phase 0 is the rapid depolarization by the influx of Na⫹. Phase 1 consists of rapid repolarization by efflux of K⫹. Phase 2, named the plateau phase, is the longest phase and marks Ca2⫹ entry. Phase 3 allows final repolarization of the cell by restoration of the membrane potential. Phase 4 is the stable phase with a resting potential of ⫾90 mV (190). Mg2⫹ is

mainly important in phases 2 and 3 of the myocardial action potential, exerting its effect on K⫹ and Ca2⫹ channels. In phase 2, Mg2⫹ inhibits L-type Ca2⫹ channels (Cav1.2) to prevent Ca2⫹ overload and cell toxicity (558). Mg2⫹ can bind a COOH-terminal EF hand motif of the channel and thereby influences the Ca2⫹ current (63). The effects of Mg2⫹ on the current through the L-type Ca2⫹ channels (ICaL) may depend on the channel’s phosphorylation state, since phosphatase treatment decreases the inhibitory effects of Mg2⫹ (547). In phase 3, delayed rectifier K⫹ channels repolarize the cell by rapid-activating (IKr) and slow-activating (IKs) currents. High [Mg2⫹i] inhibits IK currents in frog and guinea pig cardiomyocytes (128, 563). This effect probably depends on the slow-activating component of the current, since rapid-activating currents seem insensitive to

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FIGURE 8. Magnesium in heart. Mg2⫹ influences phase 2 and phase 3 of the cardiac action potential by inhibiting L-type Ca2⫹ channels (phase 2) and delayed rectifier K currents (phase 3). Moreover, Mg2⫹ directly influences the cardiac muscle contraction by antagonizing Ca2⫹ binding of troponin C and calmodulin. It further modifies Ca2⫹ availability by affecting NCX and SERCA activity. Inset: the cardiac action potential. The numbers indicate the phases of the action potential. Tc, troponin C; CaM, calmodulin; NCX, Na⫹-Ca2⫹-exchanger; SERCA, sarcoplasmatic/endoplasmic reticulum Ca2⫹-ATPase; RYR, ryanodine receptor.

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MAGNESIUM IN MAN Mg2⫹ inhibition (499). The intracellular block of inward rectifier K⫹ channels Kir2.1 and Kir2.2 by Mg2⫹ substantially influences phase 3 and phase 4 of the action potential (556). This block of the IK1 current is relieved by high extracellular K⫹ concentrations (56).

An important role of Mg2⫹ in heart and vasculature function is a substantial vasodilatory effect that has been reported in animal and human studies (18, 161, 512, 513). Although the results from animal studies suggest that Mg2⫹-induced vasodilation is due to the regulation of NO synthesis, human studies show that it is independent of NO activity (512, 513). Moreover, Mg2⫹ deficiency promotes oxidative stress notably in endothelial cells (118, 561), resulting in increased reactive oxygen species (ROS) and cytotoxicity (590). In contrast, high Mg2⫹ in the cell increases eNOS activity and suppresses the synthesis of vasoconstrictor endothelin-1 (277, 327). In conditions of low Mg2⫹induced oxidative stress, the endothelium develops a state of permanent inflammation, which is marked by increased NF␬B activitiy (153). NF␬B is the master regulator of transcription of cytokines and pro-inflammatorty genes, including IL-1␣. As a result of this local inflammation, the vessel wall will recruit monocytes and trigger the proliferation and migration of vascular smooth muscle cells. These processes are facilitated by the increased expression of matrix metalloproteases 2 and 9 in low Mg2⫹ conditions (153, 382). Eventually low Mg2⫹ concentrations may, therefore, result in atherosclerosis, vascular calcifications, or thrombosis. 1. Coronary artery disease Over the last 20 years, an increasing number of studies have demonstrated that low serum Mg2⫹ levels and low Mg2⫹ intake are associated with an increased risk of coronary

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2. Myocardial infarction In the 1970s, a pioneering paper by Abraham et al. (9) associated myocardial infarction with a significant drop in serum Mg2⫹. Indeed, low serum Mg2⫹ levels have been associated with an increased risk of acute myocardial infarction (AMI) (484). The role of Mg2⫹ in preventing myocardial infarction may be caused by relaxing endothelial and smooth muscle cells in the heart and vasculature (18, 161, 512). Moreover, heart rate variability is a risk factor for AMI and Mg2⫹ may prevent arrhythmia (474, 484). Several studies have addressed the effect of Mg2⫹ on myocardial infarction. In the 1980s, studies reported a 20% reduction of infarct size in Mg2⫹-treated patients, and decreased mortality after Mg2⫹ infusion (352, 415). Several follow-up studies suggested that decreased rates of arrhythmias after infarction explain the lower mortality (76, 487). After these initial promising results, several clinical trials have addressed this subject. The Leicester Intravenous Magnesium Intervention Trial 2 (LIMIT-2) included 2,316 AMI patients and found 24% reduced mortality after 28 days in the Mg2⫹ group (95% CI: 1– 43%) (569). Moreover, two smaller studies by Shechter and colleagues reported reduced mortality rates of 50 and 40% (469, 470). Contrary to these findings, in the fourth Infarct Survival and Magnesium in Coronies (ISIS-4) study, a randomized factorial trial in 58,050 patients showed no beneficial effects of intravenous Mg2⫹ administration on survival (4). The results from the ISIS-4 study were called into question because

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In recent years an increasing amount of attention has been directed to the role of [Mg2⫹i] in cardiac excitation-contraction coupling (342). Mg2⫹ has often been considered as a natural Ca2⫹ antagonist, since it can compete with Ca2⫹ for binding sites in proteins and Ca2⫹ transporters (257). The effect of Mg2⫹ on cardiomyocytes is mainly explained by its role of Ca2⫹ mobilization. Mg2⫹ binds calmodulin, troponin C, and parvalbumin, and therefore a reduced [Mg2⫹i] may result in alterations in the unbound Ca2⫹ fraction (15). Mg2⫹ may also affect the main Ca2⫹-transporting proteins in the cardiomyocytes. Mg2⫹ acts as substrate in a complex with ATP for cardiac Ca2⫹-ATPases and alters the affinity of Na⫹-Ca2⫹ exchanger type 1 for Ca2⫹ (NCX1) (55, 58, 342). There is a dearth of physiological studies on the effect of Mg2⫹ on NCX1 and SERCA activity, and available studies mainly rely on modeling and in vitro experiments. Nevertheless, tight regulation of [Mg2⫹i] in cardiac cells is necessary for optimal cardiac function. This is substantiated by the fact that high [Mg2⫹i] can cause cardiac arrest, and by the impressive capacity of cardiomyocytes to maintain constant [Mg2⫹i] (506, 521).

artery disease (CAD), artherosclerosis, and metabolic syndrome (8, 222, 316, 587). Low serum Mg2⫹ levels have been associated with a higher mortality risk in CAD patients (162). There may be several ways in which Mg2⫹ supplementation benefits patients with CAD. Since Mg2⫹ has a strong anti-inflammatory role, Mg2⫹ results in an improved lipid profile, reduced free oxygen radicals, and improved endothelial function (317, 490). Mg2⫹ prevents blood clotting by reducing platelet aggregation (437), and it has a strong vasodilator effect (512, 513). These properties make Mg2⫹ an important factor in the development and management of CAD. Mg2⫹ improves several aspects of vascular function in CAD. Reduced serum Mg2⫹ concentrations are associated with an increase in carotid intimamedia thickness and risk for sudden cardiac death (218, 324, 391). In a randomized, double-blind, placebo-controlled study of 50 CAD patients, oral Mg2⫹ supplementation ameliorated endothelial function (472). Moreover, Mg2⫹ reduced platelet-induced thrombosis in a randomized prospective, double-blind, crossover, and placebo-controlled study in 42 CAD patients (471). Six months of Mg2⫹ supplementation increased maximal oxygen uptake ˙O (V 2 max) and left ventricular ejection fraction (LVEF) in 53 CAD patients (401). Taken together, these studies suggest that Mg2⫹ levels should be closely monitored in CAD patients and propose Mg2⫹ as potential drug to improve quality of life in CAD patients.


DE BAAIJ ET AL. the statistical analysis did not reflect the heterogeneous studies used in the analysis, the low mortality in the placebo-group was indicative of a low-risk comparison group, and the late time-point of Mg2⫹ administration, namely, after and not during reperfusion, was at odds with animal data demonstrating the effectiveness of Mg2⫹ (463). However, also a second large-scale randomized double-blind study with 6,213 patients and an earlier time point of Mg2⫹ infusion (3.8 h compared with 8 h in ISIS-4) also failed to show a decrease on 30-day mortality rates (2). Indeed, a recent meta-analysis within the Cochrane collaboration concludes that there is no beneficial effect of Mg2⫹ on mortality in AMI patients (OR 0.99, 95% CI 0.94 to 1.04) (312). However, it should be noted that the ISIS-4 study provides 72% of the power in this analysis and that the Mg2⫹ doses used within the analyzed studies differ significantly. Nevertheless, current guidelines do not recommend Mg2⫹ administration in AMI patients. 3. Arrhythmia

4. Preeclampsia Since the 1950s, intravenous MgSO4 administration has gradually become the standard treatment for preeclampsia and eclampsia, and nowadays the treatment is widely advocated by the World Health Organization (223, 407, 594). The mechanisms of action underlying the effect of Mg2⫹ in the treatment of these patients are largely unknown. Mg2⫹ may reduce preeclampsia by its effect as vasodilator in the vasculature, but it cannot be excluded that Mg2⫹ also functions as an anticonvulsant through blockade of the NMDA receptor and reduces cerebral edema (147). Recent Cochrane systematic reviews showed that MgSO4 treatment in preeclamptic women reduced the risk for eclampsia by ⬎50% (RR 0.41, 95% CI 0.29 – 0.58), and there was a trend towards lower maternal mortality (RR 0.54, 95% CI 0.26 –1.10) (130). MgSO4 demonstrated similar ratios for reduced risk for eclamptic convulsions comparable to anticonvulsant medication, with 59% compared with diazepam (RR 0.41, 95% CI 0.29 – 0.58) and 66% compared with phenytoin (RR 0.34, 95% CI 0.24 – 0.49) (131, 132). Moreover, a recent meta-analysis of “real-world” use of MgSO4 for the treatment of preeclampsia confirmed the results from the clinical trials and showed ⬃50% reduction of eclampsia risk in most studies (337). Interestingly, although Mg2⫹ was successful in preventing eclampsia, it did not change the risk of death or disability for children at 18 mo (RR 1.06, 95% CI 0.90 –1.25) or the risk of death or disability for women at 2 yr (RR 0.84, 95% CI 0.60 –1.18) (5, 6). 5. Hypertension Low serum Mg2⫹ levels are frequently linked to high blood pressure (30, 267, 270). Intracellular Mg2⫹ may reduce the intracellular Ca2⫹ concentration within vascular smooth muscle cells. This Mg2⫹-induced vasodilation is thought to be the mechanism by which Mg2⫹ alters the blood pressure. Moreover, high extracellular Mg2⫹ reduces the endothelin-1 expression and causes an increase in prostacyclin (PGI2) levels, contributing to vasodilation (27, 59, 303, 447). Additionally, Mg2⫹ inhibits the production of NO (392). Mg2⫹ was first used to lower blood pressure in 1925, when Mg2⫹ infusion was found to lower blood pressure by reducing the peripheral vascular resistance (53). Several studies have shown that oral Mg2⫹ intake reduces both systolic and diastolic blood pressure (260, 275, 559); however, other studies fail to see such an effect (72, 152). A systematic review of the Cochrane Hypertension Group reported a small reduction of diastolic blood pressure (DBP; ⫺2.2 mmHg, 95% CI ⫺3.4 to ⫺0.9), but not of the systolic blood pressure (SBP; ⫺1.3 mmHg, 95% CI ⫺4.0 to 1.5) (119). Another meta-analysis detected a small but dose-

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In 1935, Dr. Zwillinger was the first to report an antiarrhythmic effect of Mg2⫹, and since then sporadic reports of patients treated with Mg2⫹ have appeared in the literature (595). However, the field suffers from a lack of largescale randomized controlled trials, and therefore the exact clinical benefit of Mg2⫹ in treatment of arrhythmia remains to be determined. Mg2⫹ is known to have a function in regulating cardiac K⫹ and Ca2⫹ channels, so it affects the cardiac action potential. As a result, hypomagnesemia in itself has been proposed as a cause of arrhythmia, specifically in combination with stress or alcoholism (362, 524). Clinical studies have demonstrated that treatment success strongly depends on the type of arrhythmia (232). Atrial fibrillation is one of the most common and dangerous complications after cardiac surgery. In the last few decades, several small-scale studies have examined the effect of Mg2⫹ in preventing these fibrillations (93). Meta-analysis of these studies concluded that Mg2⫹ infusion may prevent atrial fibrillations (201, 474). Therefore, the European Association for Cardiothoracic Surgery and the Canadian Cardiovascular Society recommend prophylaxis with intravenous MgSO4. However, recent reports point to problems associated with many studies at the level of double-blinding, primary outcome, and intention-to-treat analysis. When only high quality studies are included, Mg2⫹ does not have a preventive effect on atrial fibrillations (OR: 0.94, 95% CI: 0.61–1.44) (93). A similar discrepancy between low- and high-quality studies has been noted for studies addressing the effects of Mg2⫹ on supraventricular arrhythmias (108). Interestingly, for treatment of torsades des pointes, Mg2⫹ has been implemented as a first line of treatment after several studies in the 1980s showed beneficial effects (395, 527, 528). However, due to the absence of large-scale clinical trials, optimal doses for treatment are still under debate (211, 243, 244). Other arrhythmias, including refractory ventricular fibrillation and monomor-

phic ventricular tachycardia, are insensitive to Mg2⫹ treatment (150, 220).


MAGNESIUM IN MAN dependent effect of Mg2⫹ on blood pressure, for each 10 mmol/day ⫺4.3 mmHg SBP (95% CI ⫺6.3 to ⫺2.2) and ⫺2.3 mmHg DBP (95% CI ⫺4.9 to 0.0) (262). However, the outcomes may be biased by the inclusion of poor quality studies that tend to overestimate the effects. In contrast, a meta-analysis of a subset of studies, including patients on antihypertensive drugs with high blood pressure (SBP ⬎155 mmHg) reports much stronger effects of oral Mg2⫹ treatment on SBP (⫺18.7 mmHg, 95% CI ⫺14.95 to ⫺22.45) and DBP (⫺10.9 mmHg, 95% CI ⫺8.73 to ⫺13.1) (425). These results suggest that Mg2⫹ may be beneficial for certain subgroups of hypertensive patients and that comparing the highly heterogeneous studies may underestimate the effects of Mg2⫹ in these groups. 6. Vascular calcification

D. Magnesium in Muscle Mg2⫹ mainly exerts its effects on skeletal muscle function as a Ca2⫹ antagonist on Ca2⫹-permeable channels and Ca2⫹binding proteins. Muscle contraction is a highly Ca2⫹-dependent process, initiated Ca2⫹ release from the sarcoplasmic reticulum. Ca2⫹ binds to troponin C and myosin to induce the conformational changes of these proteins that will result in contraction (193). Mg2⫹ competes for the Ca2⫹-binding sites on these proteins. Although the affinity of troponin and myosin for Mg2⫹ is much lower than for Ca2⫹ (292), the effects of Mg2⫹ are not negligible (239,

22

Moreover, as a cofactor of ATP, Mg2⫹ availability is essential for the function of the ryanodine receptor (RyR), which allows rapid Ca2⫹ release from the ER, and Ca2⫹-ATPase of sarcoplasmic reticulum (SERCA), which mediates the return of Ca2⫹ to the SR after contraction. Intracellular Mg2⫹ and Ca2⫹ concentrations determine how many ATP molecules bind to the RyR, which determines the opening of these channel receptors and the release of Ca2⫹ (117). SERCA also depends on Mg2⫹ as cofactor of ATP. Additionally, Mg2⫹ can bind to the Ca2⫹ binding pocket of SERCA (584). The role of Mg2⫹ in the regulation of the Na⫹-Ca2⫹ exchanger (NCX) has been poorly studied so far. 1. Muscle cramps Muscle cramps are a recurrent and prominent symptom in patients with severe/chronic hypomagnesemia (49, 215). Although the role of Mg2⫹ in the pathogenesis of muscle cramps is not completely understood, it is hypothesized that Mg2⫹ directly influences muscular contractions by antagonizing Ca2⫹-binding proteins. Moreover, Mg2⫹-deficient patients may suffer from neuronal hyperexcitability that can contribute to muscular contraction. Mg2⫹ has consequently been considered as treatment for muscle cramps in several studies. However, there is little evidence that Mg2⫹ may relieve muscle cramps in the general population. A recent Cochrane systematic review and meta-analysis of all published studies shows no significant reduction in the number of cramps after Mg2⫹ treatment (⫺3.93%, 95% CI: ⫺21.12 to 13.26%) (168). In contrast, a Cochrane review from 2002 demonstrated that Mg2⫹ might be beneficial for muscle cramps in pregnancy (OR 0.18, 95% CI 0.05– 0.60) (583). Both meta-analyses are limited by a relatively small patient population. Large-scale studies are necessary to ascertain the utility of Mg2⫹ for specific subpopulations or disease-related muscle cramps.

E. Magnesium in Pancreas Mg2⫹ has been implicated in both endocrine and exocrine functioning of the pancreas. In the pancreatic acini, intracellular Mg2⫹ antagonizes Ca2⫹-activated signaling events and enzyme secretion (573). It is known that ACh and cholecystokinin 8 (CCK8) evoke an increase in intracellular Ca2⫹, which in turn activates calmodulin, resulting in the phosphorylation of proteins on the enzyme-containing ves-

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Vascular calcification is frequently observed in patients suffering from chronic kidney disease (CKD) (452). Calcifications are a major contributor to cardiovascular death that accounts for 50% of all deaths in CKD (522). Vascular calcification is the consequence of a disturbed mineral metabolism including increased serum Pi levels. Increased serum levels of FGF23 and PTH enhance the formation of calicification. Low serum Mg2⫹ levels are associated with vascular calcification, and hemodialysis patients with higher serum Mg2⫹ levels show higher survival (258, 259). Although the mechanisms of action are not completely understood, there are two contributing factors: 1) Mg2⫹ prevents the formation and deposition of Ca/P nanocrystals and the development of appatite structures (83); and 2) Mg2⫹ inhibits the transdifferentiation of the smooth muscle cells in the vessel well into osteoblast-like cells (282). In both processes Mg2⫹ prevents vascular calcifiction, and thus hypomagnesemic patients are at risk. Therefore, Mg2⫹ supplementation has been proposed as Pi-binder to reduce vascular calcification in CKD patients. Several studies have shown that combined administration of Ca2⫹ and Mg2⫹ is as effective as standard treatment options (252). In the recent CALMAG study comparing MgCO3/Ca(OAc)2 with Sevalamer-HCl in 200 hemodialysis patients, both treatments were effective in reducing serum Pi levels without increasing Ca2⫹ levels (106).

403). In the resting state, Mg2⫹ is present in concentrations 10,000 times higher than Ca2⫹ in muscle cells (292); therefore, Mg2⫹ will occupy all Ca2⫹ binding sites, and it is only after Ca2⫹ is released from the sarcoplasmic reticulum that Mg2⫹ is replaced. However, in Mg2⫹-deficient conditions, not as much Ca2⫹ is required to displace Mg2⫹, resulting in hypercontractibility, which presents as muscle cramps and spasms in the clinic.


DE BAAIJ ET AL. icles. These vesicles will migrate towards the plasma membrane for exocytosis and secretion. Interestingly, ACh and CCK8 activation cause a marked Mg2⫹ efflux, allowing Ca2⫹ signaling to occur (483, 564). Its antagonizing role may be explained by inhibition of Ca2⫹ transporting proteins such as SERCA, PMCA, and Ca⫹-ATPases (120, 584).

1. Diabetes Patients with diabetes mellitus type 2 often have low serum Mg2⫹ levels (36, 491, 541). These low serum levels are associated with poor disease outcome and may even increase mortality (98). Hypomagnesemia may contribute to the development of diabetes mellitus type 2 by increasing insulin resistance. Insulin receptors (IR) are part of the family of tyrosine kinase receptors, and the kinase function is dependent on the binding of two Mg2⫹ ions (249). Upon activation of the IR, a complex intracellular signaling cascade is activated and mediated via insulin receptor substrate proteins (505). In low Mg2⫹ conditions, activation of the IR may result in diminished signal transduction, contributing to insulin resistance. Studies with hypomagnesemic rats bear this out, as lower IR phosphorylation was detected, although differences between individual organs were reported (419, 498). It has also been proposed that increased expression of other effectors such as IL-1, IL-6, IL-8, TNF-␣, norepinephrine, epinephrine, and ROS may contribute to insulin resistance in Mg2⫹ deficiency (206). Interestingly, common SNPs in the TRPM6 gene are associated with an increased risk of developing diabetes mellitus type 2 (489). TRPM6 cannot be activated by insulin when these SNPs are present (361). These results suggest that Mg2⫹ levels may influence the onset and development of diabetes mellitus type 2. Several studies have examined the clinical effects of oral Mg2⫹ supplementation on glycemic control in diabetes mellitus type 2 patients. Some of these studies demonstrate impressive effects in reducing glucated hemoglobin (HbA1c) levels and fasting glucose concentrations (385, 423), but other studies show no improvement of gly-

F. Magnesium in Liver The role of Mg2⫹ in the liver is poorly studied. However, given that many of the enzymatic reactions that take place in the hepatocytes are dependent on Mg2⫹, particularly in fat metabolism, the importance of Mg2⫹ should not be underestimated. Mg2⫹ supplementation has been reported to reduce alanine aminotranferase (ALT) levels in obese women with hypomagnesemia (421). However, this result could not be reproduced in normomagnesemic patients, although a lower dose of Mg2⫹ was used in this study (271). The first reports of hypomagnesemia in liver diseases such as cirrhosis and nonalcoholic fatty liver disease suggest that liver function contributes to proper intestinal Mg2⫹ absorption (286, 526). Currently, the first clinical trials are being initiated to test the effects of Mg2⫹ supplementation in patients with liver cirrhosis.

G. Magnesium in Immunity Mg2⫹ is considered as an anti-inflammatory agent that reduces the expression and release of substance P and other proinflammatory molecules. Mg2⫹ also influences acquired immunity by regulating the proliferation and development of lymphocytes (156). Deletion of the TRPM7 Mg2⫹ channel caused cell death in the chicken B cell line DT40, which could be partially rescued by culturing the cells in high Mg2⫹ containing medium (455). In a mouse model with a specific T-cell deletion of TRPM7, T lymphocyte development was blocked at the CD4⫺CD8⫺ stage, resulting in decreased CD4⫹ and CD4⫹CD8⫹ cells in the thymus (266). Moreover, mutations in the MagT1 Mg2⫹ channel are causative for immunodeficiency and have been associated with decreased CD4⫹ T lymphocyte levels (311). These results suggest that Mg2⫹ is essential for T lymphocyte development and proliferation. 1. X-linked T-cell immunodeficiency Patients with X-linked immunodeficiency with Mg2⫹ defect, Epstein-Barr virus infection and neoplasia (XMEN) have mutations in MagT1 (79, 311). They present with chronic Epstein-Barr virus infections, low CD4⫹ T-cell counts, and defective T-lymphocyte activation. These effects are hypothesized to result from a loss of PLC␥1 activation due to reduced Mg2⫹ influx via MagT1 (311). Recent studies in asthma pa-

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In the islets of Langerhans, Mg2⫹ may influence the secretion of insulin, although experimental results are conflicting as to whether insulin secretion is increased or decreased. Milner and Hales (344) reported that Mg2⫹ reduced insulin secretion in an ex vivo model using rabbit pancreas. These results were confirmed in rat pancreas and rat insulinoma cells (99, 357). However, in rats, one study found increased insulin secretion in Mg2⫹-deficient rats, while other studies in Mg2⫹-deficient rats did not report alterations in plasma insulin concentrations (202, 338, 418). In addition, patients with low serum Mg2⫹ levels show decreased insulin secretion (422). The discrepancies among different experiments may be explained by the Ca2⫹ availability in each of the models. Since the effect of Mg2⫹ on insulin can be explained by its Ca2⫹ antagonizing role, it may not depend on the Mg2⫹ concentration itself, but on the cytosolic Ca2⫹/Mg2⫹ ratio.

cemic control (107, 204). A meta-analysis of 8 studies, including a total of 370 patients, evidenced a reduction of fasting glucose levels (⫺0.56 mM; 95% CI, ⫺1.10 to ⫺0.01), reflected in a nonsignificant (P ⫽ 0.1) reduction of HbA1c levels (⫺0.31%, 95% CI, ⫺0.81 to 0.19) (488). All together, these results indicate that Mg2⫹ supplementation may be a promising avenue for achieving glycemic control in diabetes patients.


MAGNESIUM IN MAN tients confirm the importance of Mg2⫹ availability for CD4⫹ function (315). An increased risk in T-cell lymphoblastic leukemia has been associated with Mg2⫹ deficiency (441). However, the role of Mg2⫹ in T-cell signaling needs to be investigated before further conclusions can be drawn. Special attention should be given to the involvement of other Mg2⫹ carriers, since TRPM7-deficient T cells seem protected from Fas-receptor-induced apoptosis (115).

H. Magnesium in Bone Bone hydroxyapatite structures mainly consist of Pi and Ca2⫹ and are bound by Mg2⫹ ions at the surface of the hydroxyapatite crystals. Mg2⫹ increases the solubility of the minerals and thereby acts on the crystal size and formation (443). Crystals in Mg2⫹-deficient bone are larger, and the bone may therefore be brittle and more susceptible to fractures (89). Moreover, Mg2⫹ stimulates osteoblast proliferation, suggesting that Mg2⫹ deficiency results in decreased bone formation (320) 2⫹ (FIGURE 4). The role of bone in Mg homeostasis is described in more detail in section IIIB.

Several studies have associated low serum Mg2⫹ values with osteoporosis (61, 213). Although most studies have been performed in postmenopausal women, there is some evidence of low bone Mg2⫹ content in elderly subjects. In this study the patients had normal serum Mg2⫹ levels, but displayed significantly increased retention in a loading/tolerance test (91). A few small-scale studies have examined the effects of oral Mg2⫹ supplementation (200 –750 mg/day) on bone mineral density (BMD) in patients with osteoporosis. In a pioneering study in 1991, daily administration of 600 mg Mg resulted in an 11% increased BMD after 12 mo (10). However, many other supplements including 500 mg/day Ca were simultaneously used, making it difficult to distinguish the effects of Mg2⫹. Subsequently, multiple studies have examined the effect of Mg2⫹ supplementation in different populations (138, 436, 494). Mg2⫹ seems to increase BMD in all of the studies, although the effects are relatively small (1–3%) and the small study sizes limit the conclusions that can be made from them. Testing the effect of Mg2⫹ supplementation in large cohorts of osteoporosis patients may further establish Mg2⫹ supplements to treat osteoporosis.

V. DISTURBANCES OF MAGNESIUM HOMEOSTASIS Over the last decade, clinical interest in Mg2⫹ has been growing. Mg2⫹ deficiency has been associated with a wide range of diseases including diabetes mellitus type 2, hypertension, migraine, and depression. Therefore, the Mg2⫹ balance in patients is clinically significant; however, Mg2⫹ status in patients is not routinely determined. When Mg2⫹ is assessed in pa-

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However, serum Mg2⫹ levels represent ⬍1% of the body Mg2⫹ content, and therefore, it is a poor predictor of the body Mg2⫹ status. Additionally, the Mg2⫹ concentration in red blood cells is higher than in the serum (1.65–2.65 mM), and extra care should be taken to prevent hemolysis, which can result in a misrepresentation of total serum Mg2⫹ (520). In a recent systematic review, red blood cell (RBC) Mg2⫹ content has been proposed as an alternative measure to determine Mg2⫹ status, since its value is strongly affected by alterations in dietary Mg2⫹ intake in six studies (n ⫽ 130) (565). Based on the limited changes of ionized serum concentration after dietary Mg2⫹ supplementation or depletion, the authors reject ionized Mg2⫹ as marker for patient Mg2⫹ status. However, the rationale that alterations in dietary Mg2⫹ intake necessarily result in a physiologically relevant effect in Mg2⫹ availability is questionable, since the kidney and bone have a large capacity to compensate for reduced Mg2⫹ absorption. Only after a long-term depletion, patients may develop a clinically relevant hypomagnesemia. However, the opposite also holds true; patients may be severely Mg2⫹ deficient, although serum or RBC Mg2⫹ levels are normal. In this case, the Mg2⫹ concentrations in bones and soft tissues are severly decreased, after long-term compensatory Mg2⫹ release to keep serum Mg2⫹ levels within normal range. To identify such patients, a Mg2⫹ loading test has been proposed in which acute oral Mg2⫹ administration is used to assess Mg2⫹ retention (363). In this test, the serum Mg2⫹ concentration and fecal Mg2⫹ excretion are calculated to determine intestinal Mg2⫹ absorption. Mg2⫹-deficient patients will have lower bone Mg2⫹ content and therefore show high Mg2⫹ retention (90). Thus the loading test allows quantification of the exchangeable pool of Mg2⫹, which is more sensitive than serum Mg2⫹ concentrations. However, this test is rarely used in clinic, and as a result, standardization is lacking. Within a research setting, a urine excretion of ⬍60% of the Mg2⫹ load is generally considered normal. If a Mg2⫹ disturbance is suspected, urinary Mg2⫹ concentrations are regularly determined. It should be noted that reliable urine Mg2⫹ determinations require at least a complete 24-h sampling, since the circadian rhythm influences renal Mg2⫹ excretion (158). The results of urine Mg2⫹ tests may provide information about the cause of Mg2⫹ deficiencies; normal or high urinary excretion indicates renal Mg2⫹ wasting, whereas low Mg2⫹ excretion suggests reduced intestinal absorption. This information can then be used to guide treatment plans.

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1. Osteoporosis

tients, total serum Mg2⫹ is the most commonly measured parameter. However, total serum Mg2⫹ levels do not necessarily represent body Mg2⫹ availability, since ionized Mg2⫹ determines the bioactive fraction. Only 2% of the clinical laboratories in the United States offer ionized Mg2⫹ tests, thus leaving total serum Mg2⫹ as the most used clinical representative of the patient’s Mg2⫹ status (139).


DE BAAIJ ET AL. Importantly, physicians must be aware that urinary Mg2⫹ concentrations are poor indicators of a patient’s Mg2⫹ status when kidney function is reduced. In several pathophysiological circumstances such as diabetes and chronic kidney disease, filtration may be altered. Additionally, the use of certain drugs including diuretics may cause bias in determining a patient’s Mg2⫹ status.

1. Drug-induced hypermagnesemia Only a few drug-induced cases of hypermagnesemia have been reported, and most of them are the direct consequence of the administration of Mg2⫹ itself or Mg2⫹-containing drugs (TABLE 4). A) EPSOM SALTS.

A. Hypermagnesemia

Table 3. Symptoms of Mg2⫹ disturbances Concentration

Clinical Manifestation

Hypomagnesemia ⬍0.7 mM

⬍0.4 mM

Neuromuscular irritability Hypocalcemia Hypokalemia Tetany Seizures Arrhythmias Hypermagnesemia

⬎1.2 mM ⬎2 mM

⬎3 mM

⬎5 M

Lethargy Drowsiness Flushing Nausea and vomiting Diminished deep tendon reflex Somnolence Loss of deep tendon reflexes Hypotension ECG changes Complete heart block Cardiac arrest Apnea Paralysis Coma Death

B) CATHARTICS, LAXATIVES, AND ENEMA. Several Mg

2⫹

derivates have been used as cathartics, laxatives, and enemas with the similar goals of softening the stool and easing defecation by increasing their water content. For a long time magnesium citrate [Mg3(C6H5O7)2] was the most commonly used cathartic. Due to the risk of developing hypermagnesemia and other electrolyte disturbances, polyethylene glycol and electrolyte lavage solutions are currently the first drugs of choice (378, 451). Several Mg2⫹-containing substances [Mg3(C6H5O7)2, Mg(OH)2, MgSO4] have been used as laxatives. Mg2⫹ substances elevate the intestinal osmotic pressure, but also act on aquaporin-3 expression and thus increase water permeability (373). Mg2⫹ has been used as a component of enemas to treat constipation. However, both use of Mg2⫹ as a laxative and as an enema may result in fatal hypermagnesemia (413, 521, 586). Therefore, Mg2⫹ administration should be avoided in patients with reduced kidney function, and serum Mg2⫹ should be closely monitored during treatment.

B. Hypomagnesemia Hypomagnesemia is generally defined as serum Mg2⫹ levels below 0.7 mM. Patients suffer from nonspecific symptoms such as depression, tiredness, muscle spasms, and muscle weakness, and diagnosis therefore may take years (TABLE 3) (177, 523). Only severe Mg2⫹ depletion (⬍0.4 mM) may lead to cardiac arrhythmias, tetany, and seizures. Secondary to hypomagnesemia, disturbances in K⫹ and Ca2⫹ handling are often detected. Hypokalemia can be attributed to increased renal K⫹ secretion via ROMK in the connecting tubule (CNT) and collecting duct (CD) (248). Low intracellular Mg2⫹ levels release the Mg2⫹-dependent inhibition of ROMK channels, resulting in increased renal K⫹ secretion. Hypocalcemia can be explained by low PTH levels due to altered activation of the CaSR (574). Hypomagnesemia is generally treated by oral Mg2⫹ supplementation (⫾360 mg/day), although oral Mg2⫹ intake may cause diarrhea at high doses. Intravenous Mg2⫹ supplementation may be more effective, but this treatment has the disadvantage that it requires regular hospital visits. The

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Serum Mg2⫹ levels above 1.1 mM are generally considered hypermagnesemic. Hypermagnesemia may be clinically observed in patients suffering from nausea, vomiting, lethargy, headaches, and/or flushing. When Mg2⫹ levels rise above 3.0 mM it may even cause severe cardiac defects that are characterized by brachycardia, hypotension, and prolongation of the QRS, PR, and QT intervals (TABLE 3). Extreme hypermagnesemia can therefore result in coma, asystole, and death by cardiac arrest. However, hypermagnesemia is rare and until now no genetic causes for it have been identified. Hypermagnesemic patients are often treated by infusion of Ca2⫹ salts to antagonize the cardiac effects of Mg2⫹ (433). Also the efficacy of hemodialysis in the treatment of acute hypermagnesemia has been illustrated (228, 379).

Epsom salts consist of MgSO4 and are generally used as bath salts or a home remedy against abdominal pain, constipation, and muscle strains. Excessive ingestion of Epsom salts may result in Mg2⫹ overdose and hypermagnesemia. As a result, several fatal cases have been reported in literature (52, 231).


MAGNESIUM IN MAN treatment regimen of intravenous Mg2⫹ supplementation normally consists of 8 –12 g of magnesium sulfate in the first 24 h followed by 4 – 6 g/day for 3 or 4 days (523). When serum Mg2⫹ levels are extremely low or are accompanied by hypokalemia, Mg2⫹ supplementation may not be sufficient to restore normal Mg2⫹ levels. In that case, patients are often cosupplemented with K⫹ or receive amiloride to prevent K⫹ secretion. The following section of this review will focus on the causes of hypomagnesemia. Drug-induced and genetic hypomagnesemia will be distinhished from more general origins of Mg2⫹ deficiency (TABLES 4 AND 5). 1. General causes of hypomagnesemia A) DIETARY MG

2⫹

INTAKE. Estimations state that up to 60% of American do not meet daily Mg2⫹ requirements (163, 281). Chronic inadequate intake of Mg2⫹ leads to hypomagnesemia. Consumption of Mg2⫹-rich foods such as kelp,

nuts, green vegetables, and whole grains may prevent this. However, insufficient Mg2⫹ intake may also be caused by pathological conditions such as anorexia nervosa (51). B) VOMITING AND DIARRHEA.

Vomiting and diarrhea may further exacerbate the effects of inadequate Mg2⫹ uptake. Specifically, diarrhea is the consequence of inadequate water reabsorption along the intestine. Since water reabsorption is a prerequisite for Mg2⫹ reabsorption to set the concentration gradient, diarrhea may result in Mg2⫹ deficiency. C) ALCOHOLISM.

Since the early 1960s it has been recognized that alcoholism may cause severe hypomagnesemia (224, 336). Patients suffer from unexplained renal Mg2⫹ wasting, but may also have reduced intestinal Mg2⫹ absorption due to vomiting or diarrhea. In hepatocytes, ethanol completely blocked Mg2⫹ uptake (75). A similar mechanism may take place in the kidney, explaining reduced Mg2⫹ reabsorption. Alcoholics often have reduced PTH levels, which may further contribute to low serum Mg2⫹ levels (7).

Class

Drug

Mechanism

Prevention/Treatment

Reference Nos.

Drug-induced hypomagnesemia Diuretics

Furosemide

TAL: reduced paracellular Mg2⫹ reabsorption DCT: reduced TRPM6 expression DCT: reduced TRPM6 activity

Thiazide EGFR inhibitors

Cetuximab

Combined K⫹ and Mg2⫹ supplementation, Switch to K⫹ and Mg2⫹-sparing diuretics such as amyloride

Mg2⫹ supplementation 341, 459, 510 Cetuximab users may switch to erlotinib Mg2⫹ supplementation Switch 144, 226 to histamine2 receptor antagonists Mg2⫹ supplementation 39, 517

Proton pump inhibitors Omeprazole, lansoprazole, pantoprazole, rabeprazole, etc.

Intestine: reduced Mg2⫹ absorption

Calcineurin inhibitors

Cyclosporin A, tacrolimus

Platinum derivates

Cisplatin, carboplatinum

DCT: reduced TRPM6 expression DCT: cell death? Reduced Mg2⫹ supplementation TRPM6 expression?

Antimicrobials

AGAs Pentamidine Rapamycin Amphotercin B Foscaret

92, 101, 127, 368

TAL: reduced paracellular Mg2⫹ supplementation Mg2⫹ reabsorption DCT: cell death? TAL: reduced paracellular Mg2⫹ reabsorption ? Mg2⫹ chelating

142, 453, 495, 593 23, 38, 169, 188, 535, 562, 585

Drug-induced hypermagnesemia Intestinal Mg2⫹ overload Intestinal Mg2⫹ overload

Epsom salt poisoning Cathartics

MgSO4 Mg3(C6H5O7)2

Laxatives

MgSO4, Mg(OH)2, Mg3(C6H5O7)2 Intestinal Mg2⫹ overload

Enema

MgSO4

Intestinal Mg2⫹ overload

Hemodialysis 52, 231 Switch to polyethyleneglycol or 378, 451 electrolyte lavage solutions Switch to bulk (fiber-based) 413, 521, 586 laxatives Switch to fleet (sodium phosphate) enema

EGFR, epidermal growth factor receptor; TAL, thick ascending limb of Henle’s loop; DCT, distal convoluted tubule; TRPM6, transient receptor potential melastatin type 6; AGAs, aminoglycoside antibiotics.

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Table 4. Drug-induced Mg2⫹ disturbances


DE BAAIJ ET AL.

Table 5. Genetic causes of hypomagnesemia Gene

Protein

Disease

OMIM

Inh.

Segment

Blood Urine Blood Mg2ⴙ Mg2ⴙ Ca2ⴙ

Urine Ca2ⴙ

Other Symptoms

Reference Nos.

Human genetic Mg2⫹ disorders in TAL CLDN16

Claudin 16 FHHNC type 1 CLDN19 Claudin 19 FHHNC type 2 SLC12A1 NKCC2 Bartter type 1

248250

R

TAL

2

Nephrocalcinosis, renal failure

480

248190

R

TAL

2

293

601678

R

TAL

2

KCNJ1

ROMK

Bartter type 2

241200

R

TAL

2

CLCNKB

ClC-Kb

Bartter type 3

607364

R

TAL

2

BSND

Barttin

Bartter type 4

602522

R

TAL

2

Nephrocalcinosis, renal failure, visual impairment Na⫹ wasting, hypokalemic alkalosis, high renin/aldosterone Na⫹ wasting, hypokalemic alkalosis, high renin/aldosterone Na⫹ wasting, hypokalemic alkalosis, high renin/aldosterone Na⫹ wasting, hypokalemic alkalosis, high renin/aldosterone

478

479

477

50

Human genetic Mg2⫹ disorders in DCT TRPM6

HSH

602014

DCT

2

2

EGF CNNM2 KCNA1

EGF CNNM2 Kv1.1

IRH HSMR ADH

611718 R DCT 613882 D/R DCT 176260 D DCT

2 2 2

– –

– – –

– – –

KCNJ10

Kir4.1

SeSAME/ 612780 EAST

R

DCT

2

2

FXYD2 HNF1B

FXYD2 HNF1␤

IDH RCAD

154020 137920

D D

DCT DCT

2 2

– –

2 2

PCBD1

PCBD1

RCAD-like 264070

R

DCT

2

Gitelman 263800 syndrome

R

DCT

2

2

SLC12A3 NCC

R

Seizures, muscle spasms, mental retardation Seizures, mental retardation Seizures, mental retardation Muscle cramps, tetany, myokymia Hypokalemia, metabolic alkalosis, sensorineural deafness, seizures, ataxia, mental retardation Convulsions Renal cysts, MODY5, renal malformations Transient hyperphenylalaninemia, MODY5-like Hypokalemia, metabolic alkalosis, tetany, chondrocalcinosis

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TRPM6

454, 543 197 497 176 54, 458

339 11 154

481

SLC, solute carrier; NKCC2, Na⫹-K⫹-2Cl⫺ cotransporter; TRPM6, transient receptor potential melastatin type 6; EGF, epidermal growth factor; CNNM2, cyclin M2; FXYD2, FXYD domain containing ion transport regulator 2; HNF1B, hepatocyte nuclear factor 1B; PCBD1, pterin-4-alpha-carbinolamine dehydratase; NCC, Na⫹-Cl⫺ cotransporter; FHHNC, familial hypomagnesemia with hypercalciuria and nephrocalcinosis; HSH, hypomagnesemia with secondary hypocalcemia; IRH, isolated recessive hypomagnesemia; HSMR, hypomagnesemia with seizures and mental retardation; ADH, autosomal dominant hypomagnesemia; SeSAME, sensorineural deafness, seizures, ataxia, mental retardation, and electrolyte imbalance; EAST, epilepsy, ataxia, sensorineural deafness, and tubulopathy; IDH, isolated dominant hypomagnesemia; RCAD, renal cysts and diabetes; OMIM: online Mendelian inheritance in man; D, dominant; R, recessive; TAL, thick ascending limb of Henle’s loop; DCT, distal convoluted tubule; MODY, maturity-onset diabetes of the young.

2. Genetic hypomagnesemia A) CLDN16. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis type I (FHHNC type I; OMIM 248250) is caused by mutations in claudin 16, previously known as paracellin-1 (480). Patients suffer from renal Mg2⫹ wasting, hypomagnesemia, renal Ca2⫹ wasting, renal parenchymal calcification (nephrocalcinosis), and renal

failure. Serum and urinary Na⫹, K⫹, Cl⫺, and HCO3⫺ values are initially normal, but may be indirectly affected after progression of renal failure. Sometimes these symptoms are extended to urinary tract infections, kidney stones, and hyperuricemia; Mg2⫹ supplementation is not capable of restoring normal serum Mg2⫹ levels or slowing disease progression (567). A few dozen different mutations have been reported, all characterized by a recessive mode of inheri-

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MAGNESIUM IN MAN tance (177). All symptoms can be traced to the TAL, the main site for paracellular Ca2⫹ and Mg2⫹ reabsorption. Claudin 16 is part of the tight junction between the cells, and disruption of these tight junctions results in a lack of Ca2⫹ and Mg2⫹ reabsorption in TAL, which can only partially be compensated in the downstream DCT and CNT segments.

C) TRPM6.

Hypomagnesemia with secondary hypocalcemia (HSH; OMIM 602014) is characterized by extremely low serum Mg2⫹ levels (0.1– 0.3 mM) accompanied by low serum Ca2⫹ levels, which result in severe muscular and neurological complications including seizures and mental retardation (454, 543). The disorder was first characterized by Paunier and colleagues in 1968 and later mapped to a region at chromosome 9q in 1997 (390, 544). In 2002, two independent groups identified mutations in TRPM6 to be causative for HSH (454, 543). TRPM6 forms the epithelial Mg2⫹ channel responsible for transcellular Mg2⫹ transport in the colon and DCT segment of the kidney (540). Therefore, mutations result in reduced intestinal absorption and renal Mg2⫹ wasting. HSH has an autosomal-recessive mode of inheritance, and currently a few dozen mutations have been found. Patients are generally treated with Mg2⫹ supplements and antiepileptic drugs against seizures. Serum Mg2⫹ levels improve after supplementation, but did not recover to normal levels (297).

E) KCNA1.

In a Brazilian family, mutations in KCNA1 encoding voltage-gated K⫹ channel Kv1.1. cause autosomal dominant hypomagnesemia (OMIM 176260) (176). The patient presented in the clinic with muscle cramps, muscle, weakness, tetanic episodes, and tremor. Serum Mg2⫹ values were low (0.37 mM), whereas other electrolytes and metabolites including Na⫹, K⫹, Ca2⫹, Pi, uric acid, bicarbonate, urea, creatinine, glucose, bilirubin, aminotransferases, alkaline phosphate, and lactate dehydrogenase were all normal. Urinary creatinine clearance as well as Mg2⫹ and Ca2⫹ excretion were within normal range. KCNA1 mutations were previously linked to ataxia and myokymia (62, 146). Therefore, a cerebral MRI was performed in these patients, showing slight atrophy of the cerebral vermis. Family members suffer from myokymic discharge in electromyograph analysis, which is in line with the previously observed mixed phenotype. Intravenous Mg2⫹ infusion improved the clinical symptoms. Kv1.1 has been proposed to cause apical hyperpolarization, which allows the uptake of Mg2⫹ via TRPM6. The p.N255D (c.A763G) mutation identified in the Brazilian family disrupts Kv1.1 activity and therefore may reduce the driving force for Mg2⫹ transport. Although many KCNA1 mutations have been reported, even in residues very close to the p.N255, none of these has yet been associated with hypomagnesemia, even though Kv1.1 function is impaired (12, 263). Identification of additional hypomagnesemic families with Kv1.1 mutations may aid our understanding of Kv1.1 function in DCT. It has been suggested that other factors contribute to the apical membrane potential and may compensate for a loss of Kv1.1 function; ROMK may be one of the compensatory factors (104, 140).

D) EGF. Isolated autosomal recessive hypomagnesemia (IRH;

OMIM 611718) is caused by mutations in the EGF gene (197). In a consanguine family from Dutch origin, two sisters presented with serum Mg2⫹ levels of 0.53 and 0.56 mM and urinary Mg2⫹ values of 3.9 and 3.7 mmol/24 h, respectively (173). Serum Ca2⫹, Na⫹, K⫹, Cl⫺, HCO3⫺, and blood pH values were normal. The patients presented with epileptic seizures during their first year of life, which could be

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F) CNNM2. Mutations in CNNM2 are causative for hypomagnesemia with seizures and mental retardation (HSMR; OMIM 613882). Two unrelated families with seizures and dominant hypomagnesemia were reported to carry CNNM2 mutations (497). In these patients, serum Mg2⫹ levels range between 0.3 and 0.5 mM, but no other electrolyte disturbances were detected. The patients’ symptoms

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B) CLDN19. Similar to FHHNC type I, patients with FHHNC type 2 (OMIM 248190) suffer from severe hypomagnesemia accompanied by hypercalciuria and nephrocalcinosis. Additionally, patients have ocular defects consisting of macular colobomata, significant myopia, and horizontal nystagmus. FHHNC type 2 is caused by mutations in claudin 19, which is expressed in the TAL segment of the kidney, in parallel with claudin 16. In the initial publication from Konrad et al. (293), 12 patients from 10 families were genotyped and characterized. Remarkably, 9 of 12 patients developed chronic kidney disease or underwent kidney transplantation. Indeed, other studies confirmed that FHHNC type 2 patients are more prone to developing of CKD and develop the disease at an earlier age compared with type I patients (177). Over the years, several treatment regimens have been proposed, including oral magnesium supplementation, thiazide diuretics, and indomethacin. However, none of these treatments significantly increased serum Mg2⫹ values (177).

controlled by antiepileptic drugs. Moreover, psychomotor retardation was observed in these patients. Plasma renin activity, plasma aldosterone, and parathyroid hormone concentrations were in the normal range. Homozygosity mapping and subsequent Sanger sequencing of gene candidates led to the identification of a homozygous c.C3209T mutation in exon 22 resulting a p.P1070L missense mutation at protein level (197). This residue is particularly important for plasma membrane targeting of the EGF molecule and the mutation results in impaired basolateral sorting of pro-EGF. Therefore, TRPM6 activity is not stimulated, resulting in renal Mg2⫹ wasting (197, 515). Until now, only a single family has been described with EGF mutations, but studies with EGFR antagonists further underline the clinical importance of EGF for renal Mg2⫹ handling (discussed in detail in sect. VB3).


DE BAAIJ ET AL. include seizures, loss of consciousness, loss of muscle tone, headaches, and staring (340). Recently, five additional families were reported (28), making CNNM2 the most common genetic cause of isolated hypomagnesemia after TRPM6 and CLDN16 –19. Interestingly, in this new cohort CNNM2 mutations were linked to a phenotype of impaired brain development and mental retardation. This intellectual disability was most prominent in a family with a recessive pattern of inheritance, emphasizing the heterogeneous inheritance of CNNM2 depending on the location and severity of the mutations. HSMR patients are treated with antiepileptic drugs and Mg2⫹ supplements. Serum Mg2⫹ levels improved after supplementation, but did not reach normal levels. Although the exact function of CNNM2 remains to be elucidated, mutations can disrupt the MgATP binding domain and reduce CNNM2 membrane expression (28, 105). Recent data from patch-clamp and Mg2⫹ uptake experiments favor the hypothesis that CNNM2 does not transport Mg2⫹ itself, but rather regulates other Mg2⫹transporting proteins (28, 105, 497).

H) FXYD2.

Gene linkage studies identified the FXYD domain containing ion transport regulator 2 (FXYD2) mutations in a family with dominant isolated renal Mg2⫹ wasting (IDH; OMIM 154020) (339). The patients in this family presented with low serum Mg2⫹ values (⫾0.4 mM), while other plasma electrolytes, including Na⫹, K⫹, Ca2⫹, Cl⫺, and

I) HNF1B.

Renal cysts and diabetes syndrome (RCAD; OMIM 137920) is caused by mutations in hepatocyte nuclear factor 1␤ (HNF1␤) and consists of a heterogeneous group of symptoms including renal cysts (⫾70% of patients), maturity onset diabetes of the young subtype 5 (MODY5; ⫾50%), and hypomagnesemia (⫾45%) (11, 82). HNF1␤ is a transcription factor regulating gene expression in kidney development (331). FXYD2b expression is one of several genes that is regulated by HNF1␤ (155), which may explain its role in renal Mg2⫹ handling. However, the possibility that HNF1␤ regulates other DCT genes involved in renal Mg2⫹ transport cannot be excluded. J) PCBD1. In a small cohort of three patients, mutations in pterin-4 ␣-carbinolamine dehydratase 1 (PCBD1) have been linked to hypomagnesemia, renal Mg2⫹ wasting, and MODY5-like diabetes (154). PCBD1 mutations are known to cause transient neonatal hyperphenyalaninemia and high urinary levels of primapterin (HPABH4D; OMIM 264070) (518, 519). HPABH4D patients are diagnosed at birth by Guthrie testing and suffer from a transient, benign defect in impaired BH4 regeneration. A follow-up study of three patients at ⫾18 yr of age showed that the patients display a mild hypomagnesemia (⫾0.6 mM) and MODY5-like diabetes, but no renal cysts (154). Interestingly, serum and urinary Na⫹, K⫹, Ca2⫹, and Cl⫺ levels were within the normal range. The phenotype of the HPABH4D patients resembles that of RCAD patients, and the treatment regime consists of sulfonylureas and Mg2⫹ supplements. The origin of renal cysts in RCAD patients may be traced to the CD where HNF1␤ regulates PKHD1 (194). However, since PCBD1 is not expressed in CD, HPABH4D patients are protected from cyst formation (154). K) SLC12A3. Hypomagnesemia and hypokalemia are the cardinal symptoms of a hereditary electrolyte disorder characterized by Dr. Gitelman in 1969 that has been known since as Gitelman’s syndrome (175). Patients present with tetany, paresthesias, and chondrocalcinosis (284). The severity of the symptoms depends on the degree of hypokalemia. Except hypokalemia and hypomagnesemia, laboratory inves-

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Mutations in KCNJ10 encoding the Kir4.1 K⫹ channel can cause seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance/epilepsy, ataxia, sensorineural deafness, and renal tubulopathy syndrome (SeSAME/EAST; OMIM 612780) (54, 417, 458). Patients were reported to have marked electrolyte abnormalities, including hypokalemic metabolic alkalosis without hypertension, severe hypomagnesemia, and renal Na⫹, K⫹, and Mg2⫹ wasting. In some patients, high renin and aldosterone levels, salt craving, and polyuria were observed. Kir4.1 is hypothesized to be involved in K⫹ recycling at the basolateral membrane of DCT cells. When Kir4.1 is mutated, K⫹ availability becomes rate limiting for Na⫹-K⫹-ATPase activity. Thus the Na⫹-K⫹-ATPase will be inhibited, resulting in a reduced potential across the basolateral membrane. Consequently, Na⫹ and Mg2⫹ transport will be reduced in DCT. To compensate for this, ENaC activity in CNT will be increased at the expense of K⫹ excretion via ROMK. Therefore, SeSAME/EAST patients suffer from severe hypomagnesemia and hypokalemia. To treat the hypomagnesemia, patients are often given Mg2⫹ and K⫹ supplements, in combination with aldosterone antagonists or ENaC inhibitors (34). SeSAME/EAST patients suffer from a severe neurological phenotype consisting of tonic-clonic seizures in infancy, cerebellar ataxia, and hearing loss. Moreover, magnetic resonance imaging evidenced subtle symmetrical signal changes in the cerebellar dentate nuclei (96). G) KCNJ10.

HCO3⫺, were normal. Urinary Mg2⫹ excretion was increased, whereas Ca2⫹ excretion was slightly lowered (172). The c.G121A mutation results in a p.G41R missense mutation at the protein level, which causes misrouting of FXYD2 to the membrane (66). FXYD2 encodes for the ␥-subunit of the Na⫹-K⫹-ATPase. Although the exact role of FXYD2 in the DCT is unknown, it has been hypothesized to stabilize the Na⫹-K⫹-ATPase, influencing the membrane potential necessary for Mg2⫹ transport (345). However, other reports suggest that it may function independently as an inward rectifier channel (464). Functional analysis of the patient’s proximal tubular cells showed no differences in Na⫹, K⫹, or ATP affinity of the Na⫹-K⫹-ATPase, but demonstrated a lower FXYD2 protein expression (67).


MAGNESIUM IN MAN tigations often show metabolic alkalosis and hypocalciuria, sometimes associated with a mild hypotension and prolonged QT interval. SLC12A3 encodes the thiazide-sensitive Na⫹-Cl⫺ cotransporter (NCC), and mutations here cause Gitelman’s syndrome (165, 481). Patients with Gitelman’s syndrome are often treated with oral Mg2⫹ supplements (284). Interestingly, in some patients Mg2⫹ supplementation restores normal K⫹ levels, suggesting that hypokalemia is secondary to hypomagnesemia (205). This hypothesis is further substantiated by the NCC KO mouse, which is hypomagnesemic but does not display K⫹ disturbances under basal conditions (460). NCC KO mice have markedly reduced TRPM6 expression levels, possibly explaining the renal Mg2⫹ wasting observed in Gitelman’s syndrome (368). However, the mechanism by which a loss of NCC function results in reduced TRPM6 expression remains unresolved. It has been suggested that the atrophy of the DCT segment observed in KO mice may partially explain this phenomenon (321). L) SLC12A1, BSND, CLCNKB, AND KCNJ1.

3. Drug-induced hypomagnesemia A) DIURETICS.

Hypomagnesemia has been associated with diuretics targeting the TAL and DCT segments of the kidney. In 1968, Duarte (127) reported renal Ca2⫹ and Mg2⫹ wasting as a consequence of furosemide treatment. Furosemide inhibits the activity of NKCC2, reducing the positive transepithelial membrane potential that drives paracellular Mg2⫹ transport in TAL (408). Although the incidence of furosemide-induced hypomagnesemia is unclear, a significant number of patients who use it may suffer from Mg2⫹ wasting (92, 330). In a recent animal study, furosemide treatment did not result in hypomagnesemia since increased TRPM6 expression in the DCT was able to compensate for reduced Mg2⫹ reabsorption in TAL (530). The clinical effects of furosemide treatment on Mg2⫹ levels may, therefore, depend on the individual’s ability to compensate at DCT level.

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V) EGFR INHIBITORS.

In 2005, it was first reported that the use of the EGFR inhibitor cetuximab can result in severe hypomagnesemia (459). Cetuximab (erbitux) is a monoclonal antibody against the EGFR and is generally prescribed for the treatment of colorectal or head and neck cancer. Up to 50 – 60% of patients using cetuximab may develop, and 10 –20% display serum levels below 0.4 mM (341, 510). A recent meta-analysis showed a RR of 3.87 (396). Immediately after the first reports of cetuximab-induced hypomagnesemia, questions were raised whether the EGFR inhibitor erlotinib (tarceva) may have similar effects (16). However, as of this writing, no clinical reports on the Mg2⫹ status after the use of erlotinib are available. Animal studies demonstrated a small reduction in serum Mg2⫹ values after erlotinib administration (122). Erlotinib is generally administered as a tablet that also contains Mg2⫹ stereate. The copresence of Mg2⫹ in these tablets may explain the absence of clinical consequences of erlotinib administration on serum Mg2⫹ levels. C) PROTON PUMP INHIBITORS. In 2006, the use of protein pump inhibitors (PPI) was associated with hypomagnesemia for the first time in two separate patients receiving long-term omeprazole treatment (144). Since then, many new cases of PPI-induced hypomagnesemia have been reported (295). A recent systematic review of 36 cases demonstrated that discontinuation of PPIs resulted in recovery from hypomagnesemia within 4 days, and rechallenge led to reoccurrence within 4 days (226). Urinary Mg2⫹ excretion is low in these patients, suggesting normal kidney function and thus an effect of PPI use on intestinal Mg2⫹ absorption. In mice, administration of omeprazole increased the expression of TRPM6 in colon (300). Therefore, it was hypothesized that omeprazole may inhibit the activity of the colonic H⫹-K⫹ATPase, resulting in reduced extrusion of protons into the colon. Since TRPM6 activity increases at lower external pH, decreased proton secretion may reduce TRPM6 activity, for which increased TRPM6 expression may compensate (300, 313). However, increased TRPM6 expression may not be sufficient to prevent malabsorption of Mg2⫹ in colon in all patients. Individual variability of this compensatory mechanism may explain why only a subset of PPI users develop hypomagnesemia.

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Bartter’s syndrome was originally described by Dr. Bartter in 1962 and is characterized by salt wasting, hypokalemic alkalosis, elevated plasma renin and aldosterone levels, and low blood pressure (40). Mutations in SLC12A1, encoding NKCC2, Barttin, ClC-Kb, KCNJ1, encoding ROMK, or CaSR form the genetic basis of Bartter’s syndrome (50, 477– 479). Mild hypomagnesemia is sometimes observed in Bartter’s patients, which may be explained by a reduced driving force for paracellular Mg2⫹ reabsorption in the TAL. Compensation for reduced TAL Mg2⫹ reabsorption may take place in the DCT, which explains why Bartter’s patients often have normal Mg2⫹ levels. ClC-Kb and Barttin are also expressed in DCT, which justifies why patients with mutations in these genes more often show hypomagnesemia (261).

The use of thiazide diuretics, which target NCC in DCT, frequently induces renal Mg2⫹ wasting (366). Although most studies do not report hypomagnesemia in patients being treated with thiazide diuretics, some patient groups may be at risk (101). Patients with low initial Mg2⫹ values, such as elderly patients or patients with chronic heart failure, may develop hypomagnesemia after chronic thiazide treatment (238, 285). In mice, thiazide treatment reduces the renal expression of TRPM6, explaining the high urinary Mg2⫹ excretion (368). However, in most patients these effects may be small and the clinical consequences may depend on the patients’ basal serum Mg2⫹ values.


DE BAAIJ ET AL. D) CALCINEURIN INHIBITORS.

E) CISPLATIN/CARBOPLATIN. Already from the introduction of cisplatin (cis-diamminedichloridoplatinum) as anti-cancer therapeutic, hypomagnesemia has been reported in ⬃40%80% of treated patients (453, 593). Nephrotoxicity is a common side effect of cisplatin treatment, mainly as a consequence of proximal tubule cisplatin accumulation, which results in necrosis of the tubular cells (298). However, the effect of cisplatin on electrolyte wasting is highly specific for Mg2⫹; concomitant Ca2⫹ and K⫹ wasting is only observed in severely hypomagnesemic patients. This suggests that hypomagnesemia cannot be explained by the nephrotoxictiy and that Ca2⫹ and K⫹ disturbances are secondary to Mg2⫹ wasting. Treatment with carboplatin [paraplatin, cisdiammine(1,1-cyclobutanedicarboxylato)platinum], another platinum derivate, results in similar side effects including hypomagnesemia (142, 495). Recently, two animal studies have examined the effects of cisplatin treatment in detail (305, 529). Both observe significant downregulation of TRPM6 mRNA levels, although the causative mechanisms of reduced TRPM6 expression may differ. In the mice study of Van Angelen et al. (529), all DCT markers including parvalbumin and NCC are reduced, suggesting that cisplatin treatment induced atrophy of the DCT segment. In rats, Ledeganck et al. (305) demonstrated no effects on NCC expression, which implies that the DCT cells are still intact. Nevertheless, TRPM6 and EGF expression were reduced. Both studies show compensation of Mg2⫹ uptake in the TAL by increased expression of claudins. Generally, patients that develop hypomagnesemia during cisplatin

treatment are supplemented by adding Mg2⫹ to pre- and posthydration fluids to prevent hypomagnesemia. F) ANTIMICROBIALS.

Although several classes of antimicrobials may cause hypomagnesemia, the underlying mechanisms leading to Mg2⫹ wasting differ greatly. Aminoglycoside antibiotics (AGA) including gentamycin, neomycin, tobramycin, and amikacin may induce renal Mg2⫹ wasting (562, 585). Estimates of the incidence of hypomagnesemia as a consequence of AGA use range from 20 to 80% (157, 562). AGAs may activate the CaSR, resulting in reduced paracellular Mg2⫹ transport in the TAL and inhibition of Mg2⫹ transport in the DCT. Studies in MDCT cells show reduced PTH-activated Mg2⫹ transport (269). Moreover, animal studies have evidenced that use of AGAs cause hypomagnesemia, due to reduced expression of NKCC2 that provides the driving force for TAL Mg2⫹ transport (167, 446). In a recent study with gentamycin-treated rats, TRPM6 expression was upregulated, suggesting that the DCT compensates for reduced TAL Mg2⫹ reabsorption (307). Pentamidine is an antimicrobial against Pneumocystis jirovecii infections that are often diagnosed in AIDS patients. The use of pentamidine has been associated with severe hypomagnesemia due to renal Mg2⫹ wasting at the start of the 1990s (65, 188, 465). The exact mechanism of reduced Mg2⫹ reabsorption remains unresolved. However, pentamidine reduces ENaC activity, resulting in hyperkalemia (283). Moreover, there have been reports of tubular necrosis after pentamidine treatment (546), which may cause atrophy of the DCT segment. Rapamycin (sirolimus) is an antibiotic that is frequently used to prevent organ rejection after transplantation. Rapamycin inhibits mTOR activity, and its use has been associated with hypomagnesemia in 10 –25% of patients (23, 535). Rapamycin-treated rats exhibit reduced expression of NKCC2 (100). Interestingly, TRPM6 expression was increased in the same study. This could be compensation for the reduced Mg2⫹ uptake in TAL, but a direct effect of rapamycin on TRPM6 expression cannot be excluded. A recent in vitro study showed the opposite effect; rapamycin decreased TRPM6 expression in an EGF-dependent manner (255). Amphotericin B is an antifungal agent that has been associated with hypomagnesemia and hypokalemia (38). The mechanism underlying urinary Mg2⫹ wasting in these patients is unknown. Oral Mg2⫹ supplementation together with amiloride treatment is generally used to restore Mg2⫹ levels (178). Foscarnet inhibits viral DNA polymerases by chelating divalent cations and, therefore, its use may cause hypomagnesemia (169). Patients also suffer from hypocalcemia and

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The calcineurin inhibitors (CNI) cyclosporin A (CsA) and tacrolimus (FK506) are currently the first immunosuppressant drugs of choice after transplantation. The use of CNIs has been associated with hypertension and renal Mg2⫹ wasting (39, 517). Whereas the hypertension may be explained by an increased activity of NCC, renal Mg2⫹ wasting is not fully understood (242). Up to 90% of all patients suffer from significantly reduced serum Mg2⫹ levels after initiation of CsA treatment, and in a recent cohort even 35% of patients remained hypomagnesemic despite Mg2⫹ supplementation (39, 439, 517). In rats, CsA and FK506 treatment increased renal Mg2⫹ wasting and hypomagnesemia (29, 365). In FK506-treated rats TRPM6 mRNA is downregulated, resulting in dramatically increased Mg2⫹ excretion (365). In a recent study with CsA treatment in rats, TRPM6, TRPM7, and EGF mRNA expression were reduced, although the fractional excretion of Mg2⫹ did not significantly change (306). Interestingly, EGF treatment did not change Mg2⫹ excretion and TRPM6 expression in CsA-treated rats, whereas it reduced Mg2⫹ wasting and increased TRPM6 expression in control rats. These results suggest that CsA may interfere with the EGF signaling pathway in DCT cells. Patients receiving CNI treatment are generally supplemented with Mg2⫹ to prevent hypomagnesemia.


MAGNESIUM IN MAN hypokalemia, which may be secondary to the Mg2⫹ disturbances (253, 369). Until now, no studies have examined the effect of forscarnet on the expression of renal ion transporters. It would be interesting to examine whether forscarnet exhibits effects beyond its chelating function.

VI. CONCLUDING REMARKS

Genetic and drug-induced disorders of Mg2⫹ homeostasis have enhanced the knowledge on Mg2⫹ (re)absorption in the kidney and intestine. These studies form a perfect example of the powerful interaction of clinical and fundamental studies. For instance, the increased knowledge on the role of EGF in renal Mg2⫹ handling has resulted in the standardization of Mg2⫹ measurements in patients using EGFR blockers. This resulted in early detection of Mg2⫹ disturbances and changes in treatment strategies. Through synergistic clinical and fundamental efforts in the fields of brain, heart, and lung Mg2⫹ research, the unexplained role of Mg2⫹ in, among others, migraine, depression, epilepsy, COPD, and hypertension, may be elucidated. Over the last decades Mg2⫹ research has been centered around the kidney and the intestine. By extending the field to the heart, brain, and lungs and by involving both fundamental and clinical researchers, Mg2⫹ will never be thought of as “a forgotten cation” anymore.

ACKNOWLEDGMENTS We acknowledge the careful reading of the manuscript by Dr. Anke Lameris, Dr. Jenny van der Wijst, Cas van der Made, and Judy Lin. Robert Boensma drew the illustrations. Address for reprint requests and other correspondence: R. J. M. Bindels, Radboud University Medical Center, Dept. of Physiology 286, PO Box 9101, 6500 HB Nijmegen, The Netherlands (e-mail: Rene.Bindels@radboudumc.nl).

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This work was supported by grants from the Netherlands Organization for Scientific Research [NWO Vici Grant (to J. G. J. Hoenderop), 016.130.668, and ZonMw 9120.8026], Dutch Kidney Foundation (CP10.11, IP10.27, IP11.46, and PhD12.14), and EURenOmics funding from the European Union Seventh Framework Program (FP7/ 2007–2013, agreement no. 305608).

DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the authors.

REFERENCES 1. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academies Press, 1997. 2. Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in the Magnesium in Coronaries (MAGIC) Trial: a randomised controlled trial. Lancet 360: 1189 –1196, 2002. 3. Expert Panel Report 3 (E.P.R.-3): Guidelines for the Diagnosis, and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol 120: S94 –138, 2007. 4. ISIS4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival). Collaborative Group Lancet 345: 669 – 685, 1995. 5. The Magpie Trial: a randomised trial comparing magnesium sulphate with placebo for pre-eclampsia. Outcome for children at 18 months. Br J Obstet Gynaecol 114: 289 – 299, 2007. 6. The Magpie Trial: a randomised trial comparing magnesium sulphate with placebo for pre-eclampsia. Outcome for women at 2 years. Br J Obstet Gynaecol 114: 300 –309, 2007. 7. Abbott L, Nadler J, Rude RK. Magnesium deficiency in alcoholism: possible contribution to osteoporosis and cardiovascular disease in alcoholics. Alcoholism Clin Exp Res 18: 1076 –1082, 1994. 8. Abbott RD, Ando F, Masaki KH, Tung KH, Rodriguez BL, Petrovitch H, Yano K, Curb JD. Dietary magnesium intake and the future risk of coronary heart disease (the Honolulu Heart Program). Am J Cardiol 92: 665– 669, 2003. 9. Abraham AS, Eylath U, Weinstein M, Czaczkes E. Serum magnesium levels in patients with acute myocardial infarction. N Engl J Med 296: 862– 863, 1977. 10. Abraham GE. The importance of magnesium in the management of primary postmenopausal osteoporosis. J Nutr Environ Med 2: 165–178, 1991. 11. Adalat S, Woolf AS, Johnstone KA, Wirsing A, Harries LW, Long DA, Hennekam RC, Ledermann SE, Rees L, van’t Hoff W, Marks SD, Trompeter RS, Tullus K, Winyard PJ, Cansick J, Mushtaq I, Dhillon HK, Bingham C, Edghill EL, Shroff R, Stanescu H, Ryffel GU, Ellard S, Bockenhauer D. HNF1B mutations associate with hypomagnesemia and renal magnesium wasting. J Am Soc Nephrol 20: 1123–1131, 2009. 12. Adelman JP, Bond CT, Pessia M, Maylie J. Episodic ataxia results from voltage-dependent potassium channels with altered functions. Neuron 15: 1449 –1454, 1995. 13. Alderton A, Davies P, Illman K, Brown DR. Ancient conserved domain protein-1 binds copper and modifies its retention in cells. J Neurochem 103: 312–321, 2007. 14. Alfrey AC, Miller NL, Trow R. Effect of age and magnesium depletion on bone magnesium pools in rats. J Clin Invest 54: 1074 –1081, 1974. 15. Allouche D, Parello J, Sanejouand YH. Ca2⫹/Mg2⫹ exchange in parvalbumin and other EF-hand proteins. A theoretical study. J Mol Biol 285: 857– 873, 1999.

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Over the last decade, Mg2⫹ has been considered as a treatment for several major diseases including preeclampsia, stroke, myocardial infarction, and asthma in several largescale clinical trials. These findings have raised interest in Mg2⫹ among neurologists, cardiologists, and pneumologists. Nevertheless, Mg2⫹ levels are still not determined routinely in daily clinical practice, eventhough up to 60% of all critically ill patients are Mg2⫹ deficient (84, 145). Serum Mg2⫹ should be determined standardly, alongside Na⫹, K⫹, and Ca2⫹ measurements in patients. Mg2⫹ disturbances can cause muscle cramps, arrhythmias, and seizures, and therefore, Mg2⫹ should be considered when patients present in clinic with these symptoms. However, the molecular mechanisms underlying the effects of Mg2⫹ in brain, heart, and lung are still largely unknown. Finding the molecular basis of the role of Mg2⫹ in these diseases may further extend the significance of Mg2⫹ therapies in clinic.

GRANTS


DE BAAIJ ET AL. 16. Altundag K, Altundag O, Baptista MZ, Turen S, Atik MA. Re: Cetuximab therapy and symptomatic hypomagnesemia. J Natl Cancer Inst 97: 1791–1792, 2005. 17. Altura BM, Gebrewold A, Zhang A, Altura BT. Low extracellular magnesium ions induce lipid peroxidation and activation of nuclear factor-kappa B in canine cerebral vascular smooth muscle: possible relation to traumatic brain injury and strokes. Neurosci Lett 341: 189 –192, 2003. 18. Altura BT, Altura BM. Endothelium-dependent relaxation in coronary arteries requires magnesium ions. Br J Pharmacol 91: 449 – 451, 1987. 19. Altura BT, Memon ZI, Zhang A, Cheng TP, Silverman R, Cracco RQ, Altura BM. Low levels of serum ionized magnesium are found in patients early after stroke which result in rapid elevation in cytosolic free calcium and spasm in cerebral vascular muscle cells. Neurosci Lett 230: 37– 40, 1997. 20. Amasheh S, Fromm M, Gunzel D. Claudins of intestine and nephron: a correlation of molecular tight junction structure and barrier function. Acta Physiol 201: 133–140, 2011. 21. Amin M, Abdel-Fattah M, Zaghloul SS. Magnesium concentration in acute asthmatic children. Iranian J Pediatr 22: 463– 467, 2012. 22. Anastassopoulou J, Theophanides T. Magnesium-DNA interactions and the possible relation of magnesium to carcinogenesis. Irradiation and free radicals. Crit Rev Oncol/ Hematol 42: 79 –91, 2002. 23. Andoh TF, Burdmann EA, Fransechini N, Houghton DC, Bennett WM. Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506. Kidney Int 50: 1110 – 1117, 1996.

25. Arango MF, Bainbridge D. Magnesium for acute traumatic brain injury. Cochrane Database Systematic Rev CD005400, 2008. 26. Ariza AC, Bobadilla N, Diaz L, Avila E, Larrea F, Halhali A. Placental gene expression of calcitonin gene-related peptide and nitric oxide synthases in preeclampsia: effects of magnesium sulfate. Magnesium Res 22: 44 – 49, 2009. 27. Ariza AC, Ponce X, Gonzalez-Gonzalez ME, Larrea F, Halhali A. Effects of magnesium sulphate on placental expression of endothelin 1 and its receptors in preeclampsia. Clin Biochem 40: 976 –980, 2007. 28. Arjona FJ, De Baaij JHF, Schlingmann KP, Lameris ALL, Van Wijk E, Flik G, Regele S, Korenke GC, Nephytou B, Rust S, Reintjes N, Konrad M, Bindels RJM, Hoenderop JGJ. CNNM2 Mutations cause Impaired Brain Development and Seizures in Patients with Hypomagnesemia. PLoS Genet 10: e1004267, 2014. 29. Asai T, Nakatani T, Yamanaka S, Tamada S, Kishimoto T, Tashiro K, Nakao T, Okamura M, Kim S, Iwao H, Miura K. Magnesium supplementation prevents experimental chronic cyclosporine a nephrotoxicity via renin-angiotensin system independent mechanism. Transplantation 74: 784 –791, 2002. 30. Ascherio A, Hennekens C, Willett WC, Sacks F, Rosner B, Manson J, Witteman J, Stampfer MJ. Prospective study of nutritional factors, blood pressure, and hypertension among US women. Hypertension 27: 1065–1072, 1996.

38. Barton CH, Pahl M, Vaziri ND, Cesario T. Renal magnesium wasting associated with amphotericin B therapy. Am J Med 77: 471– 474, 1984. 39. Barton CH, Vaziri ND, Martin DC, Choi S, Alikhani S. Hypomagnesemia and renal magnesium wasting in renal transplant recipients receiving cyclosporine. Am J Med 83: 693– 699, 1987. 40. Bartter FC, Pronove P, Gill JR Jr, Maccardle RC. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med 33: 811– 828, 1962. 41. Barzilay G, Mol CD, Robson CN, Walker LJ, Cunningham RP, Tainer JA, Hickson ID. Identification of critical active-site residues in the multifunctional human DNA repair enzyme HAP1. Nature Struct Biol 2: 561–568, 1995. 42. Bates-Withers C, Sah R, Clapham DE. TRPM7, the Mg2⫹ inhibited channel and kinase. Adv Exp Med Biol 704: 173–183, 2011. 43. Bednarek A, Pasternak K, Karska M. Evaluation of blood serum, erythrocyte and urine magnesium concentrations in babies with pneumonia or bronchial obstructive bronchitis. Magnesium Res 16: 271–280, 2003. 44. Belge H, Gailly P, Schwaller B, Loffing J, Debaix H, Riveira-Munoz E, Beauwens R, Devogelaer JP, Hoenderop JG, Bindels RJ, Devuyst O. Renal expression of parvalbumin is critical for NaCl handling and response to diuretics. Proc Natl Acad Sci USA 104: 14849 –14854, 2007. 45. Ben-Yosef T, Belyantseva IA, Saunders TL, Hughes ED, Kawamoto K, Van Itallie CM, Beyer LA, Halsey K, Gardner DJ, Wilcox ER, Rasmussen J, Anderson JM, Dolan DF, Forge A, Raphael Y, Camper SA, Friedman TB. Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, are deaf due to cochlear hair cell degeneration. Hum Mol Genet 12: 2049 –2061, 2003. 46. Bhatt SP, Khandelwal P, Nanda S, Stoltzfus JC, Fioravanti GT. Serum magnesium is an independent predictor of frequent readmissions due to acute exacerbation of chronic obstructive pulmonary disease. Respir Med 102: 999 –1003, 2008. 47. Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Intravenous magnesium sulphate in the acute treatment of migraine without aura and migraine with aura. A randomized, double-blind, placebo-controlled study. Cephalalgia 22: 345–353, 2002. 48. Bigal ME, Walter S, Rapoport AM. Calcitonin gene-related peptide (CGRP) and migraine current understanding and state of development. Headache 53: 1230 –1244, 2013. 49. Bilbey DL, Prabhakaran VM. Muscle cramps and magnesium deficiency: case reports. Canadian Family Physician 42: 1348 –1351, 1996. 50. Birkenhager R, Otto E, Schurmann MJ, Vollmer M, Ruf EM, Maier-Lutz I, Beekmann F, Fekete A, Omran H, Feldmann D, Milford DV, Jeck N, Konrad M, Landau D, Knoers NV, Antignac C, Sudbrak R, Kispert A, Hildebrandt F. Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nature Genet 29: 310 –314, 2001. 51. Birmingham CL, Gritzner S. Heart failure in anorexia nervosa: case report and review of the literature. Eating Weight Disorders 12: e7–10, 2007.

31. Aziz HS, Blamoun AI, Shubair MK, Ismail MM, DeBari VA, Khan MA. Serum magnesium levels and acute exacerbation of chronic obstructive pulmonary disease: a retrospective study. Ann Clin Lab Sci 35: 423– 427, 2005.

52. Birrer RB, Shallash AJ, Totten V. Hypermagnesemia-induced fatality following epsom salt gargles(1). J Emergency Med 22: 185–188, 2002.

32. Bairoch A. The ENZYME database in 2000. Nucleic Acids Res 28: 304 –305, 2000.

53. Blackfan KD, Hamilton B. Uremia in acute glomerular nephritis: the cause and treatment in children. Boston Med Surg J 193: 617– 621, 1925.

33. Ban C, Junop M, Yang W. Transformation of MutL by ATP binding and hydrolysis: a switch in DNA mismatch repair. Cell 97: 85–97, 1999. 34. Bandulik S, Schmidt K, Bockenhauer D, Zdebik AA, Humberg E, Kleta R, Warth R, Reichold M. The salt-wasting phenotype of EAST syndrome, a disease with multifaceted symptoms linked to the KCNJ10 K⫹ channel. Pflügers Arch 461: 423– 435, 2011. 35. Banki CM, Vojnik M, Papp Z, Balla KZ, Arato M. Cerebrospinal fluid magnesium and calcium related to amine metabolites, diagnosis, and suicide attempts. Biol Psychiatry 20: 163–171, 1985. 36. Barbagallo M, Dominguez LJ. Magnesium metabolism in type 2 diabetes mellitus, metabolic syndrome and insulin resistance. Arch Biochem Biophys 458: 40 – 47, 2007.

54. Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, Tobin J, Lieberer E, Sterner C, Landoure G, Arora R, Sirimanna T, Thompson D, Cross JH, van’t Hoff W, Al Masri O, Tullus K, Yeung S, Anikster Y, Klootwijk E, Hubank M, Dillon MJ, Heitzmann D, Arcos-Burgos M, Knepper MA, Dobbie A, Gahl WA, Warth R, Sheridan E, Kleta R. Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl J Med 360: 1960 –1970, 2009. 55. Boyman L, Mikhasenko H, Hiller R, Khananshvili D. Kinetic and equilibrium properties of regulatory calcium sensors of NCX1 protein. J Biol Chem 284: 6185– 6193, 2009. 56. Brautigam CA, Steitz TA. Structural and functional insights provided by crystal structures of DNA polymerases and their substrate complexes. Curr Opin Struct Biol 8: 54 – 63, 1998.

Physiol Rev • VOL 95 • JANUARY 2015 • www.prv.org

33

Downloaded from on December 26, 2014

24. Angelow S, El-Husseini R, Kanzawa SA, Yu AS. Renal localization and function of the tight junction protein, claudin-19. Am J Physiol Renal Physiol 293: F166 –F177, 2007.

37. Barragan-Rodriguez L, Rodriguez-Moran M, Guerrero-Romero F. Efficacy and safety of oral magnesium supplementation in the treatment of depression in the elderly with type 2 diabetes: a randomized, equivalent trial. Magnesium Res 21: 218 –223, 2008.


MAGNESIUM IN MAN 57. Breiderhoff T, Himmerkus N, Stuiver M, Mutig K, Will C, Meij IC, Bachmann S, Bleich M, Willnow TE, Muller D. Deletion of claudin-10 (Cldn10) in the thick ascending limb impairs paracellular sodium permeability and leads to hypermagnesemia and nephrocalcinosis. Proc Natl Acad Sci USA 109: 14241–14246, 2012. 58. Breukels V, Konijnenberg A, Nabuurs SM, Touw WG, Vuister GW. The second Ca2⫹-binding domain of NCX1 binds Mg2⫹ with high affinity. Biochemistry 50: 8804 – 8812, 2011. 59. Briel RC, Lippert TH, Zahradnik HP. Action of magnesium sulfate on platelet prostacyclin interaction and prostacyclin of blood vessels. Am J Obstet Gynecol 153: 232, 1985. 60. Britton J, Pavord I, Richards K, Wisniewski A, Knox A, Lewis S, Tattersfield A, Weiss S. Dietary magnesium, lung function, wheezing, and airway hyperreactivity in a random adult population sample. Lancet 344: 357–362, 1994. 61. Brodowski J. [Levels of ionized magnesium in women with various stages of postmenopausal osteoporosis progression evaluated on the basis of densitometric examinations]. Przeglad lekarski 57: 714 –716, 2000. 62. Browne DL, Gancher ST, Nutt JG, Brunt ER, Smith EA, Kramer P, Litt M. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nature Genet 8: 136 –140, 1994. 2⫹

63. Brunet S, Scheuer T, Klevit R, Catterall WA. Modulation of CaV1.2 channels by Mg acting at an EF-hand motif in the COOH-terminal domain. J Gen Physiol 126: 311–323, 2005.

65. Burnett RJ, Reents SB. Severe hypomagnesemia induced by pentamidine. Ann Pharmacotherapy 24: 239 –240, 1990. 66. Cairo ER, Friedrich T, Swarts HG, Knoers NV, Bindels RJ, Monnens LA, Willems PH, De Pont JJ, Koenderink JB. Impaired routing of wild type FXYD2 after oligomerisation with FXYD2–G41R might explain the dominant nature of renal hypomagnesemia. Biochim Biophys Acta 1778: 398 – 404, 2008. 67. Cairo ER, Swarts HG, Wilmer MJ, Willems PH, Levtchenko EN, De Pont JJ, Koenderink JB. FXYD2 and Na,K-ATPase expression in isolated human proximal tubular cells: disturbed upregulation on renal hypomagnesemia? J Membr Biol 231: 117–124, 2009.

78. Cete Y, Dora B, Ertan C, Ozdemir C, Oktay C. A randomized prospective placebocontrolled study of intravenous magnesium sulphate vs. metoclopramide in the management of acute migraine attacks in the Emergency Department. Cephalalgia 25: 199 –204, 2005. 79. Chaigne-Delalande B, Li FY, O’Connor GM, Lukacs MJ, Jiang P, Zheng L, Shatzer A, Biancalana M, Pittaluga S, Matthews HF, Jancel TJ, Bleesing JJ, Marsh RA, Kuijpers TW, Nichols KE, Lucas CL, Nagpal S, Mehmet H, Su HC, Cohen JI, Uzel G, Lenardo MJ. Mg2⫹ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D. Science 341: 186 –191, 2013. 80. Chandler LJ, Guzman NJ, Sumners C, Crews FT. Magnesium and zinc potentiate ethanol inhibition of N-methyl-D-aspartate-stimulated nitric oxide synthase in cortical neurons. J Pharmacol Exp Ther 271: 67–75, 1994. 81. Chanimov M, Berman S, Gofman V, Weissgarten Y, Averbukh Z, Cohen ML, Vitin A, Bahar M. Total cell associated electrolyte homeostasis in rat spinal cord cells following apparently irreversible injury. Medical Science Monitor 12: BR63– 67, 2006. 82. Chen YZ, Gao Q, Zhao XZ, Chen YZ, Bennett CL, Xiong XS, Mei CL, Shi YQ, Chen XM. Systematic review of TCF2 anomalies in renal cysts and diabetes syndrome/ maturity onset diabetes of the young type 5. Chinese Med J 123: 3326 –3333, 2010. 83. Cheng PT, Grabher JJ, LeGeros RZ. Effects of magnesium on calcium phosphate formation. Magnesium 7: 123–132, 1988. 84. Chernow B, Bamberger S, Stoiko M, Vadnais M, Mills S, Hoellerich V, Warshaw AL. Hypomagnesemia in patients in postoperative intensive care. Chest 95: 391–397, 1989. 85. Chiu TK, Dickerson RE. 1 A crystal structures of B-DNA reveal sequence-specific binding and groove-specific bending of DNA by magnesium and calcium. J Mol Biol 301: 915–945, 2000. 86. Choi H, Parmar N. The use of intravenous magnesium sulphate for acute migraine: meta-analysis of randomized controlled trials. Eur J Emergency Medicine 21: 2–9, 2014. 87. Clarke RJ, Johnson JW. NMDA receptor NR2 subunit dependence of the slow component of magnesium unblock. J Neurosci 26: 5825–5834, 2006.

68. Calsou P, Salles B. Properties of damage-dependent DNA incision by nucleotide excision repair in human cell-free extracts. Nucleic Acids Res 22: 4937– 4942, 1994.

88. Cochrane DE, Douglas WW. Histamine release by exocytosis from rat mast cells on reduction of extracellular sodium: a secretory response inhibited by calcium, strontium, barium or magnesium. J Physiol 257: 433– 448, 1976.

69. Cao G, Hoenderop JG, Bindels RJ. Insight into the molecular regulation of the epithelial magnesium channel TRPM6. Curr Opin Nephrol Hypertens 17: 373–378, 2008.

89. Cohen L, Kitzes R. Infrared spectroscopy and magnesium content of bone mineral in osteoporotic women. Israel J Med Sci 17: 1123–1125, 1981.

70. Cao G, Thebault S, van der Wijst J, van der Kemp A, Lasonder E, Bindels RJ, Hoenderop JG. RACK1 inhibits TRPM6 activity via phosphorylation of the fused alphakinase domain. Curr Biol 18: 168 –176, 2008.

90. Cohen L, Laor A. Correlation between bone magnesium concentration and magnesium retention in the intravenous magnesium load test. Magnesium Res 3: 271–274, 1990.

71. Cao G, van der Wijst J, van der Kemp A, van Zeeland F, Bindels RJ, Hoenderop JG. Regulation of the epithelial Mg2⫹ channel TRPM6 by estrogen and the associated repressor protein of estrogen receptor activity (REA). J Biol Chem 284: 14788 –14795, 2009.

91. Cohen L, Laor A, Kitzes R. Bone magnesium, crystallinity index and state of body magnesium in subjects with senile osteoporosis, maturity-onset diabetes and women treated with contraceptive preparations. Magnesium 2: 70 –75, 1983.

72. Cappuccio FP, Markandu ND, Beynon GW, Shore AC, Sampson B, MacGregor GA. Lack of effect of oral magnesium on high blood pressure: a double blind study. Br Med J 291: 235–238, 1985. 73. Caspi R, Altman T, Dreher K, Fulcher CA, Subhraveti P, Keseler IM, Kothari A, Krummenacker M, Latendresse M, Mueller LA, Ong Q, Paley S, Pujar A, Shearer AG, Travers M, Weerasinghe D, Zhang P, Karp PD. The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases. Nucleic Acids Res 40: D742–753, 2012. 74. Castiglioni S, Maier JA. Magnesium and cancer: a dangerous liason. Magnesium Res 24: S92–100, 2011.

92. Cohen N, Almoznino-Sarafian D, Zaidenstein R, Alon I, Gorelik O, Shteinshnaider M, Chachashvily S, Averbukh Z, Golik A, Chen-Levy Z, Modai D. Serum magnesium aberrations in furosemide (frusemide) treated patients with congestive heart failure: pathophysiological correlates and prognostic evaluation. Heart 89: 411– 416, 2003. 93. Cook RC, Yamashita MH, Kearns M, Ramanathan K, Gin K, Humphries KH. Prophylactic magnesium does not prevent atrial fibrillation after cardiac surgery: a metaanalysis. Ann Thoracic Surg 95: 533–541, 2013. 94. Corbo J, Esses D, Bijur PE, Iannaccone R, Gallagher EJ. Randomized clinical trial of intravenous magnesium sulfate as an adjunctive medication for emergency department treatment of migraine headache. Ann Emergency Med 38: 621– 627, 2001. 95. Cowan JA. The Biological Chemistry of Magnesium. New York: VCH Publishers, 1995.

75. Cefaratti C, Young A, Romani A. Effect of ethanol administration on Mg2⫹ transport across liver plasma membrane. Alcohol 36: 5–18, 2005. 76. Ceremuzynski L, Jurgiel R, Kulakowski P, Gebalska J. Threatening arrhythmias in acute myocardial infarction are prevented by intravenous magnesium sulfate. Am Heart J 118: 1333–1334, 1989.

34

96. Cross JH, Arora R, Heckemann RA, Gunny R, Chong K, Carr L, Baldeweg T, Differ AM, Lench N, Varadkar S, Sirimanna T, Wassmer E, Hulton SA, Ognjanovic M, Ramesh V, Feather S, Kleta R, Hammers A, Bockenhauer D. Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome. Dev Med Child Neurol 55: 846 – 856, 2013.

Physiol Rev • VOL 95 • JANUARY 2015 • www.prv.org

Downloaded from on December 26, 2014

64. Brunette MG, Vigneault N, Carriere S. Micropuncture study of magnesium transport along the nephron in the young rat. Am J Physiol 227: 891– 896, 1974.

77. Cernak I, Savic VJ, Kotur J, Prokic V, Veljovic M, Grbovic D. Characterization of plasma magnesium concentration and oxidative stress following graded traumatic brain injury in humans. J Neurotrauma 17: 53– 68, 2000.


DE BAAIJ ET AL. 97. Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 11: 327–335, 2001. 98. Curiel-Garcia JA, Rodriguez-Moran M, Guerrero-Romero F. Hypomagnesemia and mortality in patients with type 2 diabetes. Magnesium Res 21: 163–166, 2008. 99. Curry DL, Joy RM, Holley DC, Bennett LL. Magnesium modulation of glucose-induced insulin secretion by the perfused rat pancreas. Endocrinology 101: 203–208, 1977. 100. Da Silva CA, de Braganca AC, Shimizu MH, Sanches TR, Fortes MA, Giorgi RR, Andrade L, Seguro AC. Rosiglitazone prevents sirolimus-induced hypomagnesemia, hypokalemia, and downregulation of NKCC2 protein expression. Am J Physiol Renal Physiol 297: F916 –F922, 2009. 101. Davies DL, Fraser R. Do diuretics cause magnesium deficiency? Br J Clin Pharmacol 36: 1–10, 1993. 102. Davy H. Electro-chemical researches, on the decomposition of the earths; with observations on the metals obtained from the alkaline earths, and on the amalgam procured from ammonia. Philos Trans R Soc Lond 98: 333–370, 1808. 103. De Baaij JH, Blanchard MG, Lavrijsen M, Leipziger J, Bindels RJ, Hoenderop JG. P2X4 receptor regulation of transient receptor potential melastatin type 6 (TRPM6) Mg channels. Pflügers Arch 466: 1941–1952, 2014. 104. De Baaij JH, Groot Koerkamp MJ, Lavrijsen M, van Zeeland F, Meijer H, Holstege FC, Bindels RJ, Hoenderop JG. Elucidation of the distal convoluted tubule transcriptome identifies new candidate genes involved in renal magnesium handling. Am J Physiol Renal Physiol 305: F1563–F1573, 2013.

106. De Francisco AL, Leidig M, Covic AC, Ketteler M, Benedyk-Lorens E, Mircescu GM, Scholz C, Ponce P, Passlick-Deetjen J. Evaluation of calcium acetate/magnesium carbonate as a phosphate binder compared with sevelamer hydrochloride in haemodialysis patients: a controlled randomized study (CALMAG study) assessing efficacy and tolerability. Nephrol Dialysis Transplant 25: 3707–3717, 2010. 107. De Lordes Lima M, Cruz T, Pousada JC, Rodrigues LE, Barbosa K, Cangucu V. The effect of magnesium supplementation in increasing doses on the control of type 2 diabetes. Diabetes Care 21: 682– 686, 1998. 108. De Oliveira GS Jr, Knautz JS, Sherwani S, McCarthy RJ. Systemic magnesium to reduce postoperative arrhythmias after coronary artery bypass graft surgery: a meta-analysis of randomized controlled trials. J Cardiothoracic Vasc Anesthesia 26: 643– 650, 2012. 109. De Valk HW, Kok PT, Struyvenberg A, van Rijn HJ, Haalboom JR, Kreukniet J, Lammers JW. Extracellular and intracellular magnesium concentrations in asthmatic patients. Eur Respir J 6: 1122–1125, 1993. 110. Deason-Towne F, Perraud AL, Schmitz C. The Mg2⫹ transporter MagT1 partially rescues cell growth and Mg2⫹ uptake in cells lacking the channel-kinase TRPM7. FEBS Lett 585: 2275–2278, 2011. 111. DeGraba TJ, Pettigrew LC. Why do neuroprotective drugs work in animals but not humans? Neurol Clinics 18: 475– 493, 2000. 112. Demirkaya S, Vural O, Dora B, Topcuoglu MA. Efficacy of intravenous magnesium sulfate in the treatment of acute migraine attacks. Headache 41: 171–177, 2001.

119. Dickinson HO, Nicolson DJ, Campbell F, Cook JV, Beyer FR, Ford GA, Mason J. Magnesium supplementation for the management of essential hypertension in adults. Cochrane Database of Systematic Rev CD004640, 2006. 120. Diederichs F. Ion homeostasis and the functional roles of SERCA reactions in stimulussecretion coupling of the pancreatic beta-cell: a mathematical simulation. Biophys Chem 134: 119 –143, 2008. 121. Dimke H, Desai P, Borovac J, Lau A, Pan W, Alexander RT. Activation of the Ca2⫹sensing receptor increases renal claudin-14 expression and urinary Ca2⫹ excretion. Am J Physiol Renal Physiol 304: F761–F769, 2013. 122. Dimke H, van der Wijst J, Alexander TR, Meijer IM, Mulder GM, van Goor H, Tejpar S, Hoenderop JG, Bindels RJ. Effects of the EGFR Inhibitor Erlotinib on Magnesium Handling. J Am Soc Nephrol 21: 1309 –1316, 2010. 123. Do Amaral AF, Rodrigues-Junior AL, Terra Filho J, Vannucchi H, Martinez JA. Effects of acute magnesium loading on pulmonary function of stable COPD patients. Med Sci Monitor 14: CR524 –529, 2008. 124. Dorhout Mees SM, Algra A, Vandertop WP, van Kooten F, Kuijsten HA, Boiten J, van Oostenbrugge RJ, Al-Shahi Salman R, Lavados PM, Rinkel GJ, van den Bergh WM. Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial. Lancet 380: 44 – 49, 2012. 125. Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Systematic Rev CD000277, 2007. 126. Dorsch NW. Cerebral arterial spasm–a clinical review. Br J Neurosurg 9: 403– 412, 1995. 127. Duarte CG. Effects of ethacrynic acid and furosemide on urinary calcium, phosphate and magnesium. Metab Clin Exp 17: 867– 876, 1968. 128. Duchatelle-Gourdon I, Hartzell HC, Lagrutta AA. Modulation of the delayed rectifier potassium current in frog cardiomyocytes by beta-adrenergic agonists and magnesium. J Physiol 415: 251–274, 1989. 129. Ducker CE, Stettler EM, French KJ, Upson JJ, Smith CD. Huntingtin interacting protein 14 is an oncogenic human protein: palmitoyl acyltransferase. Oncogene 23: 9230 – 9237, 2004. 130. Duley L, Gulmezoglu AM, Henderson-Smart DJ, Chou D. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia. Cochrane Database Systematic Rev CD000025, 2010. 131. Duley L, Henderson-Smart DJ, Chou D. Magnesium sulphate versus phenytoin for eclampsia. Cochrane Database Systematic Rev CD000128, 2010. 132. Duley L, Henderson-Smart DJ, Walker GJ, Chou D. Magnesium sulphate versus diazepam for eclampsia. Cochrane Database Systematic Rev CD000127, 2010. 133. Ebel H, Gunther T. Magnesium metabolism: a review. J Clin Chem Clin Biochem 18: 257–270, 1980. 134. Ebel H, Hollstein M, Gunther T. Role of the choline exchanger in Na⫹-independent Mg2⫹ efflux from rat erythrocytes. Biochim Biophys Acta 1559: 135–144, 2002.

113. Denis W. Determination of magnesium in blood. J Biol Chem 41: 363–365, 1920. 114. Derom ML, Sayon-Orea C, Martinez-Ortega JM, Martinez-Gonzalez MA. Magnesium and depression: a systematic review. Nutr Neurosci 16: 191–206, 2013. 115. Desai BN, Krapivinsky G, Navarro B, Krapivinsky L, Carter BC, Febvay S, Delling M, Penumaka A, Ramsey IS, Manasian Y, Clapham DE. Cleavage of TRPM7 releases the kinase domain from the ion channel and regulates its participation in Fas-induced apoptosis. Dev Cell 22: 1149 –1162, 2012. 116. Dhandapani SS, Gupta A, Vivekanandhan S, Sharma BS, Mahapatra AK. Randomized controlled trial of magnesium sulphate in severe closed traumatic brain injury. Indian J Neurotrauma 5: 27–33, 2008. 117. Dias JM, Szegedi C, Jona I, Vogel PD. Insights into the regulation of the ryanodine receptor: differential effects of Mg2⫹ and Ca2⫹ on ATP binding. Biochemistry 45: 9408 –9415, 2006.

135. Eby GA, Eby KL. Rapid recovery from major depression using magnesium treatment. Medical Hypotheses 67: 362–370, 2006. 136. Edwards L, Shirtcliffe P, Wadsworth K, Healy B, Jefferies S, Weatherall M, Beasley R, Team obotMCS. Use of nebulised magnesium sulphate as an adjuvant in the treatment of acute exacerbations of COPD in adults: a randomised double-blind placebo-controlled trial. Thorax 68: 338 –343, 2013. 137. Eimerl S, Schramm M. The quantity of calcium that appears to induce neuronal death. J Neurochem 62: 1223–1226, 1994. 138. Eisinger J, Clairet D. Effects of silicon, fluoride, etidronate and magnesium on bone mineral density: a retrospective study. Magnesium Res 6: 247–249, 1993. 139. Elin RJ. Assessment of magnesium status for diagnosis and therapy. Magnesium Res 23: S194 –198, 2010.

Physiol Rev • VOL 95 • JANUARY 2015 • www.prv.org

35

Downloaded from on December 26, 2014

105. De Baaij JH, Stuiver M, Meij IC, Lainez S, Kopplin K, Venselaar H, Muller D, Bindels RJ, Hoenderop JG. Membrane topology and intracellular processing of cyclin M2 (CNNM2). J Biol Chem 287: 13644 –13655, 2012.

118. Dickens BF, Weglicki WB, Li YS, Mak IT. Magnesium deficiency in vitro enhances free radical-induced intracellular oxidation and cytotoxicity in endothelial cells. FEBS Lett 311: 187–191, 1992.


MAGNESIUM IN MAN 140. Ellison DH. The voltage-gated K⫹ channel subunit Kv1.1 links kidney and brain. J Clin Invest 119: 763–766, 2009.

162. Ford ES. Serum magnesium and ischaemic heart disease: findings from a national sample of US adults. Int J Epidemiol 28: 645– 651, 1999.

141. Emelyanov A, Fedoseev G, Barnes PJ. Reduced intracellular magnesium concentrations in asthmatic patients. Eur Respir J 13: 38 – 40, 1999.

163. Ford ES, Mokdad AH. Dietary magnesium intake in a national sample of US adults. J Nutr 133: 2879 –2882, 2003.

142. English MW, Skinner R, Pearson AD, Price L, Wyllie R, Craft AW. Dose-related nephrotoxicity of carboplatin in children. Br J Cancer 81: 336 –341, 1999.

164. Fordtran JS, Rector FC Jr, Carter NW. The mechanisms of sodium absorption in the human small intestine. J Clin Invest 47: 884 –900, 1968.

143. Enya M, Kanoh Y, Mune T, Ishizawa M, Sarui H, Yamamoto M, Takeda N, Yasuda K, Yasujima M, Tsutaya S, Takeda J. Depressive state and paresthesia dramatically improved by intravenous MgSO4 in Gitelman’s syndrome. Intern Med 43: 410 – 414, 2004.

165. Gamba G, Saltzberg SN, Lombardi M, Miyanoshita A, Lytton J, Hediger MA, Brenner BM, Hebert SC. Primary structure and functional expression of a cDNA encoding the thiazide-sensitive, electroneutral sodium-chloride cotransporter. Proc Natl Acad Sci USA 90: 2749 –2753, 1993.

144. Epstein M, McGrath S, Law F. Proton-pump inhibitors and hypomagnesemic hypoparathyroidism. N Engl J Med 355: 1834 –1836, 2006.

166. Garfinkel L, Garfinkel D. Magnesium regulation of the glycolytic pathway and the enzymes involved. Magnesium 4: 60 –72, 1985.

145. Escuela MP, Guerra M, Anon JM, Martinez-Vizcaino V, Zapatero MD, Garcia-Jalon A, Celaya S. Total and ionized serum magnesium in critically ill patients. Intensive Care Med 31: 151–156, 2005.

167. Garland HO, Birdsey TJ, Davidge CG, McLaughlin JT, Oakes LM, Smith AJ, Harpur ES. Effects of gentamicin, neomycin and tobramycin on renal calcium and magnesium handling in two rat strains. Clin Exp Pharmacol Physiol 21: 109 –115, 1994.

146. Eunson LH, Rea R, Zuberi SM, Youroukos S, Panayiotopoulos CP, Liguori R, Avoni P, McWilliam RC, Stephenson JB, Hanna MG, Kullmann DM, Spauschus A. Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability. Ann Neurol 48: 647– 656, 2000.

168. Garrison SR, Allan GM, Sekhon RK, Musini VM, Khan KM. Magnesium for skeletal muscle cramps. Cochrane Database Systematic Rev 9: CD009402, 2012.

147. Euser AG, Cipolla MJ. Magnesium sulfate for the treatment of eclampsia: a brief review. Stroke 40: 1169 –1175, 2009.

149. Facchinetti F, Sances G, Borella P, Genazzani AR, Nappi G. Magnesium prophylaxis of menstrual migraine: effects on intracellular magnesium. Headache 31: 298 –301, 1991. 150. Farouque HM, Sanders P, Young GD. Intravenous magnesium sulfate for acute termination of sustained monomorphic ventricular tachycardia associated with coronary artery disease. Am J Cardiol 86: 1270 –1272, 2000. 151. Fei X, Hongxiang Z, Qi C, Daozhen C. Maternal plasma levels of endothelial dysfunction mediators including AM, CGRP, sICAM-1 and tHcy in pre-eclampsia. Adv Clin Exp Med 21: 573–579, 2012. 152. Ferrara LA, Iannuzzi R, Castaldo A, Iannuzzi A, Dello Russo A, Mancini M. Long-term magnesium supplementation in essential hypertension. Cardiology 81: 25–33, 1992. 153. Ferre S, Baldoli E, Leidi M, Maier JA. Magnesium deficiency promotes a pro-atherogenic phenotype in cultured human endothelial cells via activation of NFkB. Biochim Biophys Acta 1802: 952–958, 2010. 154. Ferre S, de Baaij JH, Ferreira P, Germann R, de Klerk JB, Lavrijsen M, van Zeeland F, Venselaar H, Kluijtmans LA, Hoenderop JG, Bindels RJ. Mutations in PCBD1 Cause Hypomagnesemia and Renal Magnesium Wasting. J Am Soc Nephrol 25: 574 –586, 2014. 155. Ferre S, Veenstra GJ, Bouwmeester R, Hoenderop JG, Bindels RJ. HNF-1B specifically regulates the transcription of the gammaa-subunit of the Na⫹/K⫹-ATPase. Biochem Biophys Res Commun 404: 284 –290, 2011. 156. Feske S, Skolnik EY, Prakriya M. Ion channels and transporters in lymphocyte function and immunity. Nature Rev Immunol 12: 532–547, 2012. 157. Finton CK, Bjorkland S, Zaloga GP, Uddin DE, Chernow B. Gentamicin-induced hypomagnesemia. Am Surgeon 49: 576 –578, 1983. 158. Fiorica V. Contribution of Activity to the Circadian Rhythm in Excretion of Magnesium and Calcium. Washington, DC: Federal Aviation Administration, Department of Transportation, Office of Aviation Medicine, 1968. 159. Fisher RS, Kaplan PW, Krumholz A, Lesser RP, Rosen SA, Wolff MR. Failure of highdose intravenous magnesium sulfate to control myoclonic status epilepticus. Clin Neuropharmacol 11: 537–544, 1988.

170. Gelfand EW. Role of histamine in the pathophysiology of asthma: immunomodulatory and anti-inflammatory activities of H1-receptor antagonists. Am J Med 113 Suppl 9A: 2S–7S, 2002. 171. George MS, Rosenstein D, Rubinow DR, Kling MA, Post RM. CSF magnesium in affective disorder: lack of correlation with clinical course of treatment. Psychiatry Res 51: 139 –146, 1994. 172. Geven WB, Monnens LA, Willems HL, Buijs WC, ter Haar BG. Renal magnesium wasting in two families with autosomal dominant inheritance. Kidney Int 31: 1140 – 1144, 1987. 173. Geven WB, Monnens LA, Willems JL, Buijs W, Hamel CJ. Isolated autosomal recessive renal magnesium loss in two sisters. Clin Genet 32: 398 – 402, 1987. 174. Gilliland FD, Berhane KT, Li YF, Kim DH, Margolis HG. Dietary magnesium, potassium, sodium, and children’s lung function. American journal of epidemiol 155: 125– 131, 2002. 175. Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 79: 221–235, 1966. 176. Glaudemans B, van der Wijst J, Scola RH, Lorenzoni PJ, Heister A, van der Kemp AW, Knoers NV, Hoenderop JG, Bindels RJ. A missense mutation in the Kv1.1 voltagegated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia. J Clin Invest 119: 936 –942, 2009. 177. Godron A, Harambat J, Boccio V, Mensire A, May A, Rigothier C, Couzi L, Barrou B, Godin M, Chauveau D, Faguer S, Vallet M, Cochat P, Eckart P, Guest G, Guigonis V, Houillier P, Blanchard A, Jeunemaitre X, Vargas-Poussou R. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations. Clin J Am Soc Nephrol 7: 801– 809, 2012. 178. Goldman RD, Koren G. Amphotericin B nephrotoxicity in children. J Pediatr Hematol/ Oncol 26: 421– 426, 2004. 179. Gomez-Hernandez JM, Lorra C, Pardo LA, Stuhmer W, Pongs O, Heinemann SH, Elliott AA. Molecular basis for different pore properties of potassium channels from the rat brain Kv1 gene family. Pflügers Arch 434: 661– 668, 1997. 180. Gong Y, Renigunta V, Himmerkus N, Zhang J, Renigunta A, Bleich M, Hou J. Claudin-14 regulates renal Ca2⫹ transport in response to CaSR signalling via a novel microRNA pathway. EMBO J 31: 1999 –2012, 2012.

160. Folsom AR, Hong CP. Magnesium intake and reduced risk of colon cancer in a prospective study of women. Am J Epidemiol 163: 232–235, 2006.

181. Gorji A, Scheller D, Straub H, Tegtmeier F, Köhling R, Höhling JM, Tuxhorn I, Ebner A, Wolf P, Werner Panneck H, Oppel F, Speckmann EJ. Spreading depression in human neocortical slices. Brain Res 906: 74 – 83, 2001.

161. Fonseca FA, Paiva TB, Silva EG, Ihara SS, Kasinski N, Martinez TL, Filho EE. Dietary magnesium improves endothelial dependent relaxation of balloon injured arteries in rats. Atherosclerosis 139: 237–242, 1998.

182. Goytain A, Hines RM, El-Husseini A, Quamme GA. NIPA1(SPG6), the basis for autosomal dominant form of hereditary spastic paraplegia, encodes a functional Mg2⫹ transporter. J Biol Chem 282: 8060 – 8068, 2007.

36

Physiol Rev • VOL 95 • JANUARY 2015 • www.prv.org

Downloaded from on December 26, 2014

148. Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, Sandor PS. EFNS guideline on the drug treatment of migraine–revised report of an EFNS task force. Eur J Neurol 16: 968 –981, 2009.

169. Gearhart MO, Sorg TB. Foscarnet-induced severe hypomagnesemia and other electrolyte disorders. Ann Pharmacother 27: 285–289, 1993.


DE BAAIJ ET AL. 183. Goytain A, Hines RM, Quamme GA. Huntingtin-interacting proteins, HIP14 and HIP14L, mediate dual functions, palmitoyl acyltransferase and Mg2⫹ transport. J Biol Chem 283: 33365–33374, 2008.

206. Gunther T. The biochemical function of Mg2⫹ in insulin secretion, insulin signal transduction and insulin resistance. Magnesium Res 23: 5–18, 2010.

184. Goytain A, Quamme GA. Functional characterization of ACDP2 (ancient conserved domain protein), a divalent metal transporter. Physiol Genomics 22: 382–389, 2005.

207. Gunzel D, Amasheh S, Pfaffenbach S, Richter JF, Kausalya PJ, Hunziker W, Fromm M. Claudin-16 affects transcellular Cl⫺ secretion in MDCK cells. J Physiol 587: 3777– 3793, 2009.

185. Goytain A, Quamme GA. Functional characterization of human SLC41A1, a Mg2⫹ transporter with similarity to prokaryotic MgtE Mg2⫹ transporters. Physiol Genomics 21: 337–342, 2005.

208. Gunzel D, Stuiver M, Kausalya PJ, Haisch L, Krug SM, Rosenthal R, Meij IC, Hunziker W, Fromm M, Muller D. Claudin-10 exists in six alternatively spliced isoforms that exhibit distinct localization and function. J Cell Sci 122: 1507–1517, 2009.

186. Goytain A, Quamme GA. Identification and characterization of a novel family of membrane magnesium transporters, MMgT1 and MMgT2. Am J Physiol Cell Physiol 294: C495–C502, 2008.

209. Gunzel D, Yu AS. Claudins and the modulation of tight junction permeability. Physiol Rev 93: 525–569, 2013.

187. Goytain A, Quamme GA. Identification and characterization of a novel mammalian Mg2⫹ transporter with channel-like properties. BMC Genomics 6: 48, 2005.

210. Gupta A, Eastham KM, Wrightson N, Spencer DA. Hypomagnesaemia in cystic fibrosis patients referred for lung transplant assessment. J Cystic Fibrosis 6: 360 –362, 2007.

188. Gradon JD, Fricchione L, Sepkowitz D. Severe hypomagnesemia associated with pentamidine therapy. Rev Infect Dis 13: 511–512, 1991.

211. Gupta A, Lawrence AT, Krishnan K, Kavinsky CJ, Trohman RG. Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes. Am Heart J 153: 891– 899, 2007.

189. Graham LA, Caesar JJ, Burgen AS. Gastrointestinal absorption and excretion of Mg 28 in man. Metabolism Clin Exp 9: 646 – 659, 1960.

212. Gupta SK, Manhas AS, Gupta VK, Bhatt R. Serum magnesium levels in idiopathic epilepsy. The J Assoc Physicians India 42: 456 – 457, 1994.

190. Grant AO. Cardiac ion channels. Circ Arrhythmia Electrophysiol 2: 185–194, 2009.

213. Gur A, Colpan L, Nas K, Cevik R, Sarac J, Erdogan F, Duz MZ. The role of trace minerals in the pathogenesis of postmenopausal osteoporosis and a new effect of calcitonin. J Bone Miner Metab 20: 39 – 43, 2002.

191. Green L, Kim CH, Bustamante C, Tinoco I Jr. Characterization of the mechanical unfolding of RNA pseudoknots. J Mol Biol 375: 511–528, 2008.

193. Greising SM, Gransee HM, Mantilla CB, Sieck GC. Systems biology of skeletal muscle: fiber type as an organizing principle. Wiley Interdisciplinary Rev Systems Biol Med 4: 457– 473, 2012. 194. Gresh L, Fischer E, Reimann A, Tanguy M, Garbay S, Shao X, Hiesberger T, Fiette L, Igarashi P, Yaniv M, Pontoglio M. A transcriptional network in polycystic kidney disease. EMBO J 23: 1657–1668, 2004. 195. Grew N. A Treatise of the Nature and Use of the Bitter Purging Salt Contain’d in Epsom, and Such Other Waters. London: [s.n.], 1697. 196. Groenestege WM, Hoenderop JG, van den Heuvel L, Knoers N, Bindels RJ. The epithelial Mg2⫹ channel transient receptor potential melastatin 6 is regulated by dietary Mg2⫹ content and estrogens. J Am Soc Nephrol 17: 1035–1043, 2006. 197. Groenestege WM, Thebault S, van der Wijst J, van den Berg D, Janssen R, Tejpar S, van den Heuvel LP, van Cutsem E, Hoenderop JG, Knoers NV, Bindels RJ. Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J Clin Invest 117: 2260 –2267, 2007.

214. Guther T, Vormann J, Forster R. Regulation of intracellular magnesium by Mg2⫹ efflux. Biochem Biophys Res Commun 119: 124 –131, 1984. 215. Hall RC, Joffe JR. Hypomagnesemia. Physical and psychiatric symptoms. JAMA 224: 1749 –1751, 1973. 216. Hardwick LL, Jones MR, Buddington RK, Clemens RA, Lee DB. Comparison of calcium and magnesium absorption: in vivo and in vitro studies. Am J Physiol Gastrointest Liver Physiol 259: G720 –G726, 1990. 217. Hardy S, Uetani N, Wong N, Kostantin E, Labbe DP, Begin LR, Mes-Masson A, Miranda-Saavedra D, Tremblay ML. The protein tyrosine phosphatase PRL-2 interacts with the magnesium transporter CNNM3 to promote oncogenesis. Oncogene 2014; doi:10.1038/onc.2014.33. 218. Hashimoto T, Hara A, Ohkubo T, Kikuya M, Shintani Y, Metoki H, Inoue R, Asayama K, Kanno A, Nakashita M, Terata S, Obara T, Hirose T, Hoshi H, Totsune K, Satoh H, Imai Y. Serum magnesium, ambulatory blood pressure, and carotid artery alteration: the Ohasama study. Am J Hypertens 23: 1292–1298, 2010. 219. Hashimoto Y, Nishimura Y, Maeda H, Yokoyama M. Assessment of magnesium status in patients with bronchial asthma. J Asthma 37: 489 – 496, 2000.

198. Group TETC. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 345: 1455–1463, 1995.

220. Hassan TB, Jagger C, Barnett DB. A randomised trial to investigate the efficacy of magnesium sulphate for refractory ventricular fibrillation. Emergency Med J 19: 57– 62, 2002.

199. Grubbs RD. Effect of epidermal growth factor on magnesium homeostasis in BC3H1 myocytes. Am J Physiol Cell Physiol 260: C1158 –C1164, 1991.

221. Haury VG. Blood serum magnesium in bronchial asthma and its treatment by the administration of magnesium sulfate. J Lab Clin Med 26: 340 –344, 1940.

200. Gruber H, Ingram J, Norton H, Wei L, Frausto A, Mills B, Rude R. Alterations in growth plate and articular cartilage morphology are associated with reduced SOX9 localization in the magnesium-deficient rat. Biotechnic Histochem 79: 45–52, 2004.

222. He K, Liu K, Daviglus ML, Morris SJ, Loria CM, Van Horn L, Jacobs DR Jr, Savage PJ. Magnesium intake and incidence of metabolic syndrome among young adults. Circulation 113: 1675–1682, 2006.

201. Gu WJ, Wu ZJ, Wang PF, Aung LH, Yin RX. Intravenous magnesium prevents atrial fibrillation after coronary artery bypass grafting: a meta-analysis of 7 double-blind, placebo-controlled, randomized clinical trials. Trials 13: 41, 2012.

223. World Health Organization, Department of Reproductive Health and Research. Managing Complications in Pregnancy and Childbirth: A Guide for Midwives and Doctors. World Health Organization, 2003.

202. Gueux E, Rayssiguier Y. The effect of magnesium deficiency on glucose stimulated insulin secretion in rats. Horm Metab Res 15: 594 –597, 1983.

224. Heaton F, Pyrah L, Beresford C, Bryson R, Martin D. Hypomagnesaemia in chronic alcoholism. Lancet 280: 802– 805, 1962.

203. Guilbert A, Gautier M, Dhennin-Duthille I, Haren N, Sevestre H, Ouadid-Ahidouch H. Evidence that TRPM7 is required for breast cancer cell proliferation. Am J Physiol Cell Physiol 297: C493–C502, 2009.

225. Hershko A, Mamont P, Shields R, Tomkins GM. “Pleiotypic response.” Nature New Biol 232: 206 –211, 1971.

204. Gullestad L, Jacobsen T, Dolva LO. Effect of magnesium treatment on glycemic control and metabolic parameters in NIDDM patients. Diabetes Care 17: 460 – 461, 1994. 205. Gullner HG, Gill JR Jr, Bartter FC. Correction of hypokalemia by magnesium repletion in familial hypokalemic alkalosis with tubulopathy. Am J Med 71: 578 –582, 1981.

226. Hess MW, Hoenderop JG, Bindels RJ, Drenth JP. Systematic review: hypomagnesaemia induced by proton pump inhibition. Alimentary Pharmac Ther 36: 405– 413, 2012. 227. Himmerkus N, Shan Q, Goerke B, Hou J, Goodenough DA, Bleich M. Salt and acidbase metabolism in claudin-16 knockdown mice: impact for the pathophysiology of FHHNC patients. Am J Physiol Renal Physiol 295: F1641–F1647, 2008.

Physiol Rev • VOL 95 • JANUARY 2015 • www.prv.org

37

Downloaded from on December 26, 2014

192. Greger R, Velazquez H. The cortical thick ascending limb and early distal convoluted tubule in the urinary concentrating mechanism. Kidney Int 31: 590 –596, 1987.


MAGNESIUM IN MAN 228. Hirose M, Kobayashi M, Sudo S, Nakanishi K, Noda Y. Hemodialysis for toxic hypermagnesemia caused by intravenous magnesium in a woman with eclampsia and renal insufficiency. A case report. J Reprod Med 47: 1050 –1052, 2002. 229. Hirota K, Sato T, Hashimoto Y, Yoshioka H, Ohtomo N, Ishihara H, Matsuki A. Relaxant effect of magnesium and zinc on histamine-induced bronchoconstriction in dogs. Crit Care Med 27: 1159 –1163, 1999. 231. Hirschfelder AD, Haury VG. Clinical manifestations of high and low plasma magnesium: dangers of epsom salt purgation in nephritis. JAMA 102: 1138 –1141, 1934. 232. Ho KM. Intravenous magnesium for cardiac arrhythmias: jack of all trades. Magnesium Res 21: 65– 68, 2008. 233. Hoane MR. Assessment of cognitive function following magnesium therapy in the traumatically injured brain. Magnesium Res 20: 229 –236, 2007. 234. Hoenderop JG, Bindels RJ. Calciotropic and magnesiotropic TRP channels. Physiology 23: 32– 40, 2008. 235. Hoenderop JG, Bindels RJ. Epithelial Ca2⫹ and Mg2⫹ channels in health and disease. J Am Soc Nephrol 16: 15–26, 2005. 236. Hoenderop JG, Nilius B, Bindels RJ. ECaC: the gatekeeper of transepithelial Ca2⫹ transport. Biochim Biophys Acta 1600: 6 –11, 2002. 237. Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 78: 1346 – 1353, 2012.

239. Holroyde MJ, Potter JD, Solaro RJ. The calcium binding properties of phosphorylated and unphosphorylated cardiac and skeletal myosins. J Biol Chem 254: 6478 – 6482, 1979. 240. Hong BZ, Kang HS, So JN, Kim HN, Park SA, Kim SJ, Kim KR, Kwak YG. Vascular endothelial growth factor increases the intracellular magnesium. Biochem Biophys Res Commun 347: 496 –501, 2006. 241. Hong BZ, Park SA, Kim HN, Ma TZ, Kim HG, Kang HS, Kim HG, Kwak YG. Basic fibroblast growth factor increases intracellular magnesium concentration through the specific signaling pathways. Molecules Cells 28: 13–17, 2009.

252. Hutchison AJ, Wilkie M. Use of magnesium as a drug in chronic kidney disease. Clin Kidney J 5: i62–i70, 2012. 253. Huycke MM, Naguib MT, Stroemmel MM, Blick K, Monti K, Martin-Munley S, Kaufman C. A double-blind placebo-controlled crossover trial of intravenous magnesium sulfate for foscarnet-induced ionized hypocalcemia and hypomagnesemia in patients with AIDS and cytomegalovirus infection. Antimicrobial Agents Chemother 44: 2143– 2148, 2000. 254. Ikari A, Kano T, Suketa Y. Magnesium influx enhanced by nitric oxide in hypertensive rat proximal tubule cells. Biochem Biophys Res Commun 294: 710 –713, 2002. 255. Ikari A, Sanada A, Sawada H, Okude C, Tonegawa C, Sugatani J. Decrease in transient receptor potential melastatin 6 mRNA stability caused by rapamycin in renal tubular epithelial cells. Biochim Biophys Acta 1808: 1502–1508, 2011. 256. Ikonomidou C, Turski L. Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol 1: 383–386, 2002. 257. Iseri LT, French JH. Magnesium: nature’s physiologic calcium blocker. Am Heart J 108: 188 –193, 1984. 258. Ishimura E, Okuno S, Kitatani K, Tsuchida T, Yamakawa T, Shioi A, Inaba M, Nishizawa Y. Significant association between the presence of peripheral vascular calcification and lower serum magnesium in hemodialysis patients. Clin Nephrol 68: 222–227, 2007. 259. Ishimura E, Okuno S, Yamakawa T, Inaba M, Nishizawa Y. Serum magnesium concentration is a significant predictor of mortality in maintenance hemodialysis patients. Magnesium Res 20: 237–244, 2007. 260. Itoh K, Kawasaka T, Nakamura M. The effects of high oral magnesium supplementation on blood pressure, serum lipids and related variables in apparently healthy Japanese subjects. Br J Nutr 78: 737–750, 1997. 261. Jeck N, Konrad M, Peters M, Weber S, Bonzel KE, Seyberth HW. Mutations in the chloride channel gene, CLCNKB, leading to a mixed Bartter-Gitelman phenotype. Pediatr Res 48: 754 –758, 2000. 262. Jee SH, Miller ER, 3rd Guallar E, Singh VK, Appel LJ, Klag MJ. The effect of magnesium supplementation on blood pressure: a meta-analysis of randomized clinical trials. Am J Hypertens 15: 691– 696, 2002.

242. Hoorn EJ, Walsh SB, McCormick JA, Furstenberg A, Yang CL, Roeschel T, Paliege A, Howie AJ, Conley J, Bachmann S, Unwin RJ, Ellison DH. The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. Nature Med 17: 1304 –1309, 2011.

263. Jen JC, Graves TD, Hess EJ, Hanna MG, Griggs RC, Baloh RW. Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain 130: 2484 –2493, 2007.

243. Hoshino K, Ogawa K, Hishitani T, Isobe T, Eto Y. Optimal administration dosage of magnesium sulfate for torsades de pointes in children with long QT syndrome. J Am Coll Nutr 23: 497S–500S, 2004.

264. Jiang J, Li MH, Inoue K, Chu XP, Seeds J, Xiong ZG. Transient receptor potential melastatin 7-like current in human head and neck carcinoma cells: role in cell proliferation. Cancer Res 67: 10929 –10938, 2007.

244. Hoshino K, Ogawa K, Hishitani T, Isobe T, Etoh Y. Successful uses of magnesium sulfate for torsades de pointes in children with long QT syndrome. Pediatrics Int 48: 112–117, 2006.

265. Jiang SP, Wu YM, Guo SE, Lv ZQ. Decreased renal mRNA expression of TRPM6 is associated with hypomagnesemia in C57BL/6 asthmatic mice. Eur Rev Med Pharmacol Sci 14: 935–940, 2010.

245. Hou J, Paul DL, Goodenough DA. Paracellin-1 and the modulation of ion selectivity of tight junctions. J Cell Sci 118: 5109 –5118, 2005. 246. Hou J, Renigunta A, Gomes AS, Hou M, Paul DL, Waldegger S, Goodenough DA. Claudin-16 and claudin-19 interaction is required for their assembly into tight junctions and for renal reabsorption of magnesium. Proc Natl Acad Sci USA 106: 15350 – 15355, 2009. 247. Hou J, Renigunta A, Konrad M, Gomes AS, Schneeberger EE, Paul DL, Waldegger S, Goodenough DA. Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex. J Clin Invest 118: 619 – 628, 2008. 248. Huang CL, Kuo E. Mechanism of hypokalemia in magnesium deficiency. J Am Soc Nephrol 18: 2649 –2652, 2007. 249. Hubbard SR. Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog. EMBO J 16: 5572–5581, 1997. 250. Hubner CA, Holthoff K. Anion transport and GABA signaling. Front Cell Neurosci 7: 177, 2013.

38

266. Jin J, Desai BN, Navarro B, Donovan A, Andrews NC, Clapham DE. Deletion of Trpm7 disrupts embryonic development and thymopoiesis without altering Mg2⫹ homeostasis. Science 322: 756 –760, 2008. 267. Joffres MR, Reed DM, Yano K. Relationship of magnesium intake and other dietary factors to blood pressure: the Honolulu heart study. Am J Clin Nutr 45: 469 – 475, 1987. 268. Kahraman S, Ozgurtas T, Kayali H, Atabey C, Kutluay T, Timurkaynak E. Monitoring of serum ionized magnesium in neurosurgical intensive care unit: preliminary results. Clin Chim Acta 334: 211–215, 2003. 269. Kang HS, Kerstan D, Dai L, Ritchie G, Quamme GA. Aminoglycosides inhibit hormone-stimulated Mg2⫹ uptake in mouse distal convoluted tubule cells. Can J Physiol Pharmacol 78: 595– 602, 2000. 270. Kao WH, Folsom AR, Nieto FJ, Mo JP, Watson RL, Brancati FL. Serum and dietary magnesium and the risk for type 2 diabetes mellitus: the Atherosclerosis Risk in Communities Study. Arch Internal Med 159: 2151–2159, 1999.

Physiol Rev • VOL 95 • JANUARY 2015 • www.prv.org

Downloaded from on December 26, 2014

238. Hollifield JW. Thiazide treatment of hypertension. Effects of thiazide diuretics on serum potassium, magnesium, and ventricular ectopy. Am J Med 80: 8 –12, 1986.

251. Hurd TW, Otto EA, Mishima E, Gee HY, Inoue H, Inazu M, Yamada H, Halbritter J, Seki G, Konishi M, Zhou W, Yamane T, Murakami S, Caridi G, Ghiggeri G, Abe T, Hildebrandt F. Mutation of the Mg2⫹ transporter SLC41A1 results in a nephronophthisis-like phenotype. J Am Soc Nephrol 24: 967–977, 2013.


DE BAAIJ ET AL. 271. Karandish M, Tamimi M, Shayesteh AA, Haghighizadeh MH, Jalali MT. The effect of magnesium supplementation and weight loss on liver enzymes in patients with nonalcoholic fatty liver disease. J Res Med Sci 18: 2013. 272. Karbach U. Cellular-mediated and diffusive magnesium transport across the descending colon of the rat. Gastroenterology 96: 1282–1289, 1989. 273. Karbach U, Rummel W. Cellular and paracellular magnesium transport across the terminal ileum of the rat and its interaction with the calcium transport. Gastroenterology 98: 985–992, 1990.

292. Konishi M. Cytoplasmic free concentrations of Ca2⫹ and Mg2⫹ in skeletal muscle fibers at rest and during contraction. Jpn J Physiol 48: 421– 438, 1998. 293. Konrad M, Schaller A, Seelow D, Pandey AV, Waldegger S, Lesslauer A, Vitzthum H, Suzuki Y, Luk JM, Becker C, Schlingmann KP, Schmid M, Rodriguez-Soriano J, Ariceta G, Cano F, Enriquez R, Juppner H, Bakkaloglu SA, Hediger MA, Gallati S, Neuhauss SC, Nurnberg P, Weber S. Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. Am J Hum Genet 79: 949 –957, 2006. 294. Koseoglu E, Talaslioglu A, Gonul AS, Kula M. The effects of magnesium prophylaxis in migraine without aura. Magnesium Res 21: 101–108, 2008.

274. Katzberg HD, Khan AH, So YT. Assessment: symptomatic treatment for muscle cramps (an evidence-based review): report of the therapeutics and technology assessment subcommittee of the American academy of neurology. Neurology 74: 691– 696, 2010.

295. Kuipers MT, Thang HD, Arntzenius AB. Hypomagnesaemia due to use of proton pump inhibitors–a review. Netherlands J Med 67: 169 –172, 2009.

275. Kawasaki T, Itoh K, Kawasaki M. Reduction in blood pressure with a sodium-reduced, potassium- and magnesium-enriched mineral salt in subjects with mild essential hypertension. Hypertension Res 21: 235–243, 1998.

296. Kuramoto T, Kuwamura M, Tokuda S, Izawa T, Nakane Y, Kitada K, Akao M, Guenet JL, Serikawa T. A mutation in the gene encoding mitochondrial Mg2⫹ channel MRS2 results in demyelination in the rat. PLoS Genet 7: e1001262, 2011.

276. Kazaks AG, Uriu-Adams JY, Albertson TE, Stern JS. Multiple measures of magnesium status are comparable in mild asthma and control subjects. J Asthma 43: 783–788, 2006.

297. Lainez S, Schlingmann KP, van der Wijst J, Dworniczak B, van Zeeland F, Konrad M, Bindels RJ, Hoenderop JG. New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia. Eur J Hum Genet 22: 497–504, 2014.

277. Kelsen S, Hall JE, Chade AR. Endothelin-A receptor blockade slows the progression of renal injury in experimental renovascular disease. Am J Physiol Renal Physiol 301: F218 –F225, 2011.

298. Lajer H, Daugaard G. Cisplatin and hypomagnesemia. Cancer Treatment Rev 25: 47– 58, 1999.

279. Kim JH, Gelbard AS, Djordjevic B, Kim SH, Perez AG. Action of daunomycin on the nucleic acid metabolism and viability of HeLa cells. Cancer Res 28: 2437–2442, 1968. 280. Kimble RB, Srivastava S, Ross FP, Matayoshi A, Pacifici R. Estrogen deficiency increases the ability of stromal cells to support murine osteoclastogenesis via an interleukin-1and tumor necrosis factor-mediated stimulation of macrophage colony-stimulating factor production. J Biol Chem 271: 28890 –28897, 1996. 281. King DE, Mainous AG, 3rd Geesey ME, Woolson RF. Dietary magnesium and C-reactive protein levels. J Am Coll Nutr 24: 166 –171, 2005. 282. Kircelli F, Peter ME, Sevinc Ok E, Celenk FG, Yilmaz M, Steppan S, Asci G, Ok E, Passlick-Deetjen J. Magnesium reduces calcification in bovine vascular smooth muscle cells in a dose-dependent manner. Nephrol Dialysis Transplant 27: 514 –521, 2012.

300. Lameris AL, Hess MW, van Kruijsbergen I, Hoenderop JG, Bindels RJ. Omeprazole enhances the colonic expression of the Mg2⫹ transporter TRPM6. Pflügers Arch 65: 1613–1620, 2013. 301. Lameris AL, Huybers S, Kaukinen K, Makela TH, Bindels RJ, Hoenderop JG, Nevalainen PI. Expression profiling of claudins in the human gastrointestinal tract in health and during inflammatory bowel disease. Scand J Gastroenterol 48: 58 – 69, 2013. 302. Larsson SC, Bergkvist L, Wolk A. Magnesium intake in relation to risk of colorectal cancer in women. JAMA 293: 86 – 89, 2005. 303. Laurant P, Berthelot A. Endothelin-1-induced contraction in isolated aortae from normotensive and DOCA-salt hypertensive rats: effect of magnesium. Br J Pharmacol 119: 1367–1374, 1996. 304. Le Grimellec C. Micropuncture study along the proximal convoluted tubule. Electrolyte reabsorption in first convolutions. Pflügers Arch 354: 133–150, 1975.

283. Kleyman TR, Roberts C, Ling BN. A mechanism for pentamidine-induced hyperkalemia: inhibition of distal nephron sodium transport. Ann Intern Med 122: 103–106, 1995.

305. Ledeganck KJ, Boulet GA, Bogers JJ, Verpooten GA, De Winter BY. The TRPM6/EGF pathway is downregulated in a rat model of cisplatin nephrotoxicity. PloS One 8: e57016, 2013.

284. Knoers NV, Levtchenko EN. Gitelman syndrome. Orphanet J Rare Dis 3: 22, 2008.

306. Ledeganck KJ, Boulet GA, Horvath CA, Vinckx M, Bogers JJ, Van Den Bossche R, Verpooten GA, De Winter BY. Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment. Am J Physiol Renal Physiol 301: F486 –F493, 2011.

285. Kohvakka A, Heinonen L, Pietinen P, Salo H, Eisalo A. Potassium and magnesium balance in thiazide-treated cardiac patients with special reference to diet. Acta Med Scand Suppl 668: 102–109, 1982. 286. Koivisto M, Valta P, Hockerstedt K, Lindgren L. Magnesium depletion in chronic terminal liver cirrhosis. Clin Transplant 16: 325–328, 2002. 287. Kokko JP. Proximal tubule potential difference. Dependence on glucose on glucose, HCO 3, and amino acids. J Clin Invest 52: 1362–1367, 1973. 288. Kolisek M, Launay P, Beck A, Sponder G, Serafini N, Brenkus M, Froschauer EM, Martens H, Fleig A, Schweigel M. SLC41A1 is a novel mammalian Mg2⫹ carrier. J Biol Chem 283: 16235–16247, 2008. 289. Kolisek M, Nestler A, Vormann J, Schweigel-Rontgen M. Human gene SLC41A1 encodes for the Na⫹/Mg2⫹ exchanger. Am J Physiol Cell Physiol 302: C318 –C326, 2012.

307. Lee CT, Chen HC, Ng HY, Lai LW, Lien YH. Renal adaptation to gentamicin-induced mineral loss. Am J Nephrol 35: 279 –286, 2012. 308. Leo AAP. Spreading depression of activity in the cerebral cortex. J Neurophysiol 7: 359 –390, 1944. 309. Leroy J. Necessite du magnesium pour la croissance de la souris. CR Soc Biol 94: 431, 1926. 310. Levine J, Stein D, Rapoport A, Kurtzman L. High serum and cerebrospinal fluid Ca/Mg ratio in recently hospitalized acutely depressed patients. Neuropsychobiology 39: 63– 70, 1999. 311. Li FY, Chaigne-Delalande B, Kanellopoulou C, Davis JC, Matthews HF, Douek DC, Cohen JI, Uzel G, Su HC, Lenardo MJ. Second messenger role for Mg2⫹ revealed by human T-cell immunodeficiency. Nature 475: 471– 476, 2011.

290. Kolisek M, Sponder G, Mastrototaro L, Smorodchenko A, Launay P, Vormann J, Schweigel-Rontgen M. Substitution p A350V in Na⫹/Mg2⫹ exchanger SLC41A1, potentially associated with Parkinson’s Disease, is a gain-of-function mutation. PloS One 8: e71096, 2013.

312. Li J, Zhang Q, Zhang M, Egger M. Intravenous magnesium for acute myocardial infarction. Cochrane Database Systematic Rev CD002755, 2007.

291. Komaki F, Akiyama T, Yamazaki T, Kitagawa H, Nosaka S, Shirai M. Effects of intravenous magnesium infusion on in vivo release of acetylcholine and catecholamine in rat adrenal medulla. Auton Neurosci Basic Clin 177: 123–128, 2013.

313. Li M, Du J, Jiang J, Ratzan W, Su LT, Runnels LW, Yue L. Molecular determinants of Mg2⫹ and Ca2⫹ permeability and pH sensitivity in TRPM6 and TRPM7. J Biol Chem 282: 25817–25830, 2007.

Physiol Rev • VOL 95 • JANUARY 2015 • www.prv.org

39

Downloaded from on December 26, 2014

278. Kim BJ, Park EJ, Lee JH, Jeon JH, Kim SJ, So I. Suppression of transient receptor potential melastatin 7 channel induces cell death in gastric cancer. Cancer Sci 99: 2502–2509, 2008.

299. Lambers TT, Bindels RJ, Hoenderop JG. Coordinated control of renal Ca2⫹ handling. Kidney Int 69: 650 – 654, 2006.


MAGNESIUM IN MAN 314. Li M, Jiang J, Yue L. Functional characterization of homo- and heteromeric channel kinases TRPM6 and TRPM7. J Gen Physiol 127: 525–537, 2006.

336. McCollister RJ, Flink EB, Lewis MD. Urinary excretion of magnesium in man following the ingestion of ethanol. Am J Clin Nutr 12: 415– 420, 1963.

315. Liang RY, Wu W, Huang J, Jiang SP, Lin Y. Magnesium affects the cytokine secretion of CD4(⫹) T lymphocytes in acute asthma. J Asthma 49: 1012–1015, 2012.

337. McDonald SD, Lutsiv O, Dzaja N, Duley L. A systematic review of maternal and infant outcomes following magnesium sulfate for pre-eclampsia/eclampsia in real-world use. Int J Gynaecol Obstet 118: 90 –96, 2012.

316. Liao F, Folsom AR, Brancati FL. Is low magnesium concentration a risk factor for coronary heart disease? The Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J 136: 480 – 490, 1998. 317. Lin CY, Tsai PS, Hung YC, Huang CJ. L-type calcium channels are involved in mediating the anti-inflammatory effects of magnesium sulphate. Br J Anaesthesia 104: 44 – 51, 2010. 318. Lin JY, Chung SY, Lin MC, Cheng FC. Effects of magnesium sulfate on energy metabolites and glutamate in the cortex during focal cerebral ischemia and reperfusion in the gerbil monitored by a dual-probe microdialysis technique. Life Sci 71: 803– 811, 2002. 319. Lindahl T, Adams A, Fresco JR. Renaturation of transfer ribonucleic acids through site binding of magnesium. Proc Natl Acad Sci USA 55: 941–948, 1966. 320. Liu C, Yeh J, Aloia J. Magnesium directly stimulates osteoblast proliferation. J Bone Miner Res 3: S104, 1988. 321. Loffing J, Vallon V, Loffing-Cueni D, Aregger F, Richter K, Pietri L, Bloch-Faure M, Hoenderop JGJ, Shull GE, Meneton P, Kaissling B. Altered renal distal tubule structure and renal Na⫹ and Ca2⫹ handling in a mouse model for Gitelman’s Syndrome. J Am Soc Nephrol 15: 2276 –2288, 2004.

338. McNeill DA, Herbein JH, Ritchey SJ. Hepatic gluconeogenic enzymes, plasma insulin and glucagon response to magnesium deficiency and fasting. J Nutr 112: 736 –743, 1982. 339. Meij IC, Koenderink JB, van Bokhoven H, Assink KF, Groenestege WT, de Pont JJ, Bindels RJ, Monnens LA, van den Heuvel LP, Knoers NV. Dominant isolated renal magnesium loss is caused by misrouting of the Na⫹,K⫹-ATPase gamma-subunit. Nature Genet 26: 265–266, 2000. 340. Meij IC, van den Heuvel LP, Hemmes S, van der Vliet WA, Willems JL, Monnens LA, Knoers NV. Exclusion of mutations in FXYD2, CLDN16 and SLC12A3 in two families with primary renal Mg2⫹ loss. Nephrol Dialysis Transplantation 18: 512–516, 2003. 341. Melichar B, Kralickova P, Hyspler R, Kalabova H, Cerman J Jr, Holeckova P, Studentova H, Malirova E. Hypomagnesaemia in patients with metastatic colorectal carcinoma treated with cetuximab. Hepatogastroenterology 59: 366 –371, 2012. 342. Michailova AP, Belik ME, McCulloch AD. Effects of magnesium on cardiac excitationcontraction coupling. J Am Coll Nutr 23: -514S–517S, 2004.

323. Lowenstein FW, Stanton MF. Serum magnesium levels in the United States, 1971– 1974. J Am Coll Nutr 5: 399 – 414, 1986.

344. Milner RD, Hales CN. The role of calcium and magnesium in insulin secretion from rabbit pancreas studied in vitro. Diabetologia 3: 47– 49, 1967.

324. Ma J, Folsom AR, Melnick SL, Eckfeldt JH, Sharrett AR, Nabulsi AA, Hutchinson RG, Metcalf PA. Associations of serum and dietary magnesium with cardiovascular disease, hypertension, diabetes, insulin, and carotid arterial wall thickness: the ARIC study. Atherosclerosis Risk in Communities Study. J Clin Epidemiol 48: 927–940, 1995.

345. Mishra NK, Peleg Y, Cirri E, Belogus T, Lifshitz Y, Voelker DR, Apell HJ, Garty H, Karlish SJ. FXYD proteins stabilize Na,K-ATPase: amplification of specific phosphatidylserine-protein interactions. J Biol Chem 286: 9699 –9712, 2011.

325. Mahabir S, Forman MR, Dong YQ, Park Y, Hollenbeck A, Schatzkin A. Mineral intake and lung cancer risk in the NIH-American Association of Retired Persons Diet and Health study. Cancer Epidemiol Biomarkers Prevention 19: 1976 –1983, 2010. 326. Mahabir S, Wei Q, Barrera SL, Dong YQ, Etzel CJ, Spitz MR, Forman MR. Dietary magnesium and DNA repair capacity as risk factors for lung cancer. Carcinogenesis 29: 949 –956, 2008. 327. Maier JA, Bernardini D, Rayssiguier Y, Mazur A. High concentrations of magnesium modulate vascular endothelial cell behaviour in vitro. Biochim Biophys Acta 1689: 6 –12, 2004. 328. Maizels M, Blumenfeld A, Burchette R. A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial. Headache 44: 885– 890, 2004.

346. Mishra R, Rao V, Ta R, Shobeiri N, Hill CE. Mg2⫹- and MgATP-inhibited and Ca2⫹/ calmodulin-sensitive TRPM7-like current in hepatoma and hepatocytes. Am J Physiol Gastrointest Liver Physiol 297: G687–G694, 2009. 347. Misra VK, Draper DE. On the role of magnesium ions in RNA stability. Biopolymers 48: 113–135, 1998. 348. Mohammed S, Goodacre S. Intravenous and nebulised magnesium sulphate for acute asthma: systematic review and meta-analysis. Emergency Med J 24: 823– 830, 2007. 349. Monteilh-Zoller MK, Hermosura MC, Nadler MJ, Scharenberg AM, Penner R, Fleig A. TRPM7 provides an ion channel mechanism for cellular entry of trace metal ions. J Gen Physiol 121: 49 – 60, 2003. 350. Mordike BL, Ebert T. Magnesium: Properties-applications-potential. Materials Sci Eng 302: 37– 45, 2001.

329. Mandon B, Siga E, Roinel N, de Rouffignac C. Ca2⫹, Mg2⫹ and K⫹ transport in the cortical and medullary thick ascending limb of the rat nephron: influence of transepithelial voltage. Pflügers Arch 424: 558 –560, 1993.

351. Morris ME. Brain and CSF magnesium concentrations during magnesium deficit in animals and humans: neurological symptoms. Magnesium Res 5: 303–313, 1992.

330. Martin BJ, Milligan K. Diuretic-associated hypomagnesemia in the elderly. Arch Internal Med 147: 1768 –1771, 1987.

352. Morton BC, Nair RC, Smith FM, McKibbon TG, Poznanski WJ. Magnesium therapy in acute myocardial infarction: a double-blind study. Magnesium 3: 346 –352, 1984.

331. Massa F, Garbay S, Bouvier R, Sugitani Y, Noda T, Gubler MC, Heidet L, Pontoglio M, Fischer E. Hepatocyte nuclear factor 1beta controls nephron tubular development. Development 140: 886 – 896, 2013.

353. Moykkynen T, Uusi-Oukari M, Heikkila J, Lovinger DM, Luddens H, Korpi ER. Magnesium potentiation of the function of native and recombinant GABA(A) receptors. Neuroreport 12: 2175–2179, 2001.

332. Mauskop A, Altura BT, Cracco RQ, Altura BM. Intravenous magnesium sulfate relieves cluster headaches in patients with low serum ionized magnesium levels. Headache 35: 597– 600, 1995.

354. Mubagwa K, Gwanyanya A, Zakharov S, Macianskiene R. Regulation of cation channels in cardiac and smooth muscle cells by intracellular magnesium. Arch Biochem Biophys 458: 73– 89, 2007.

333. Mauskop A, Altura BT, Cracco RQ, Altura BM. Intravenous magnesium sulphate relieves migraine attacks in patients with low serum ionized magnesium levels: a pilot study. Clin Sci 89: 633– 636, 1995.

355. Muir KW. Magnesium for neuroprotection in ischaemic stroke: rationale for use and evidence of effectiveness. CNS Drugs 15: 921–930, 2001.

334. Mauskop A, Varughese J. Why all migraine patients should be treated with magnesium. J Neural Transm 119: 575–579, 2012. 335. Mayer ML, Westbrook GL, Guthrie PB. Voltage-dependent block by Mg2⫹ of NMDA responses in spinal cord neurones. Nature 309: 261–263, 1984.

40

356. Muir KW, Lees KR, Ford I, Davis S. Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. Lancet 363: 439 – 445, 2004. 357. Murakami M, Ishizuka J, Sumi S, Nickols GA, Cooper CW, Townsend CM Jr, Thompson JC. Role of extracellular magnesium in insulin secretion from rat insulinoma cells. Proc Soc Exp Biol Med 200: 490 – 494, 1992.

Physiol Rev • VOL 95 • JANUARY 2015 • www.prv.org

Downloaded from on December 26, 2014

322. Lostroh AJ, Krahl ME. Magnesium, a second messenger for insulin: ion translocation coupled to transport activity. Adv Enzyme Regul 12: 73– 81, 1974.

343. Milla PJ, Aggett PJ, Wolff OH, Harries JT. Studies in primary hypomagnesaemia: evidence for defective carrier-mediated small intestinal transport of magnesium. Gut 20: 1028 –1033, 1979.


DE BAAIJ ET AL. 358. Muroi C, Terzic A, Fortunati M, Yonekawa Y, Keller E. Magnesium sulfate in the management of patients with aneurysmal subarachnoid hemorrhage: a randomized, placebo-controlled, dose-adapted trial. Surg Neurol 69: 33–39, 2008. 359. Myrdal U, Leppert J, Edvinsson L, Ekman R, Hedner T, Nilsson H, Ringqvist I. Magnesium sulphate infusion decreases circulating calcitonin gene-related peptide (CGRP) in women with primary Raynaud’s phenomenon. Clin Physiol 14: 539 –546, 1994. 360. Nadler MJ, Hermosura MC, Inabe K, Perraud AL, Zhu Q, Stokes AJ, Kurosaki T, Kinet JP, Penner R, Scharenberg AM, Fleig A. LTRPC7 is a Mg.ATP-regulated divalent cation channel required for cell viability. Nature 411: 590 –595, 2001. 361. Nair AV, Hocher B, Verkaart S, van Zeeland F, Pfab T, Slowinski T, Chen YP, Schlingmann KP, Schaller A, Gallati S, Bindels RJ, Konrad M, Hoenderop JG. Loss of insulininduced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy. Proc Natl Acad Sci USA 109: 11324 –11329, 2012.

379. Oren S, Rapoport J, Zlotnik M, Brami JL, Heimer D, Chaimovitz C. Extreme hypermagnesemia due to ingestion of Dead Sea water. Nephron 47: 199 –201, 1987. 380. Orenstein SR, Orenstein DM. Magnesium deficiency in cystic fibrosis. Southern Med J 76: 1586, 1983. 381. Oyanagi K, Kawakami E, Kikuchi-Horie K, Ohara K, Ogata K, Takahama S, Wada M, Kihira T, Yasui M. Magnesium deficiency over generations in rats with special references to the pathogenesis of the Parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Neuropathology 26: 115–128, 2006. 382. Pages N, Gogly B, Godeau G, Igondjo-Tchen S, Maurois P, Durlach J, Bac P. Structural alterations of the vascular wall in magnesium-deficient mice. A possible role of gelatinases A (MMP-2) and B (MMP-9). Magnesium Res 16: 43– 48, 2003. 383. Pandey M, Gupta A, Baduni N, Vijfdar H, Sinha S, Jain A. Refractory status epilepticus– magnesium as rescue therapy. Anaesthesia Intensive Care 38: 962, 2010.

362. Nair RR, Nair P. Alteration of myocardial mechanics in marginal magnesium deficiency. Magnesium Res 15: 287–306, 2002.

384. Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nature Rev Neurosci 14: 383– 400, 2013.

363. Nicar MJ, Pak CY. Oral magnesium load test for the assessment of intestinal magnesium absorption. Application in control subjects, absorptive hypercalciuria, primary hyperparathyroidism, and hypoparathyroidism. Miner Electrolyte Metab 8: 44 –51, 1982.

385. Paolisso G, Sgambato S, Pizza G, Passariello N, Varricchio M, D’Onofrio F. Improved insulin response and action by chronic magnesium administration in aged NIDDM subjects. Diabetes Care 12: 265–269, 1989.

364. Nicholls DG, Sihra TS. Synaptosomes possess an exocytotic pool of glutamate. Nature 321: 772–773, 1986.

366. Nijenhuis T, Hoenderop JG, Loffing J, van der Kemp AW, van Os CH, Bindels RJ. Thiazide-induced hypocalciuria is accompanied by a decreased expression of Ca2⫹ transport proteins in kidney. Kidney Int 64: 555–564, 2003. 367. Nijenhuis T, Renkema KY, Hoenderop JG, Bindels RJ. Acid-base status determines the renal expression of Ca2⫹ and Mg2⫹ transport proteins. J Am Soc Nephrol 17: 617– 626, 2006.

387. Parry DA, Mighell AJ, El-Sayed W, Shore RC, Jalili IK, Dollfus H, Bloch-Zupan A, Carlos R, Carr IM, Downey LM, Blain KM, Mansfield DC, Shahrabi M, Heidari M, Aref P, Abbasi M, Michaelides M, Moore AT, Kirkham J, Inglehearn CF. Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta. Am J Hum Genet 84: 266 –273, 2009. 388. Parsons AA. Cortical spreading depression: its role in migraine pathogenesis and possible therapeutic intervention strategies. Curr Pain Headache Rep 8: 410 – 416, 2004. 389. Partridge IG. Studies on digestion and absorption in the intestines of growing pigs. 3. Net movements of mineral nutrients in the digestive tract. Br J Nutr 39: 527–537, 1978.

368. Nijenhuis T, Vallon V, van der Kemp AW, Loffing J, Hoenderop JG, Bindels RJ. Enhanced passive Ca2⫹ reabsorption and reduced Mg2⫹ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest 115: 1651–1658, 2005.

390. Paunier L, Radde IC, Kooh SW, Conen PE, Fraser D. Primary hypomagnesemia with secondary hypocalcemia in an infant. Pediatrics 41: 385– 402, 1968.

369. Noormohamed FH, Youle MS, Tang B, Martin-Munley S, Gazzard BG, Lant AF. Foscarnet-induced changes in plasma concentrations of total and ionized calcium and magnesium in HIV-positive patients. Antiviral Ther 1: 172–179, 1996.

391. Peacock JM, Ohira T, Post W, Sotoodehnia N, Rosamond W, Folsom AR. Serum magnesium and risk of sudden cardiac death in the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J 160: 464 – 470, 2010.

370. Nouira S, Bouida W, Grissa MH, Beltaief K, Trimech MN, Boubaker H, Marghli S, Letaief M, Boukef R. Magnesium sulfate versus ipratropium bromide in chronic obstructive pulmonary disease exacerbation: a randomized trial. Am J Ther 21: 152–158, 2014.

392. Pearson PJ, Evora PR, Seccombe JF, Schaff HV. Hypomagnesemia inhibits nitric oxide release from coronary endothelium: protective role of magnesium infusion after cardiac operations. Ann Thoracic Surg 65: 967–972, 1998.

371. Novelli F, Malagrino L, Dente FL, Paggiaro P. Efficacy of anticholinergic drugs in asthma. Expert Rev Respir Med 6: 309 –319, 2012. 372. Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307: 462– 465, 1984. 373. Okahira M, Kubota M, Iguchi K, Usui S, Hirano K. Regulation of aquaporin 3 expression by magnesium ion. Eur J Pharmacol 588: 26 –32, 2008. 374. Okayama H, Aikawa T, Okayama M, Sasaki H, Mue S, Takishima T. Bronchodilating effect of intravenous magnesium sulfate in bronchial asthma. JAMA 257: 1076 –1078, 1987. 375. Oladipo OO, Ajala MO, Okubadejo N, Danesi MA, Afonja OA. Plasma magnesium in adult Nigerian patients with epilepsy. Nigerian Postgrad Med J 10: 234 –237, 2003. 376. Olesen J. The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache. Pharmacol Ther 120: 157–171, 2008. 377. Olinger E, Schwaller B, Loffing J, Gailly P, Devuyst O. Parvalbumin: calcium and magnesium buffering in the distal nephron. Nephrol Dialysis Transplantation 27: 3988 – 3994, 2012. 378. Onishi S, Yoshino S. Cathartic-induced fatal hypermagnesemia in the elderly. Intern Med 45: 207–210, 2006.

393. Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia 16: 257–263, 1996. 394. Pelletier H, Sawaya MR, Kumar A, Wilson SH, Kraut J. Structures of ternary complexes of rat DNA polymerase beta, a DNA template-primer, and ddCTP. Science 264: 1891–1903, 1994. 395. Perticone F, Adinolfi L, Bonaduce D. Efficacy of magnesium sulfate in the treatment of torsade de pointes. Am Heart J 112: 847– 849, 1986. 396. Petrelli F, Borgonovo K, Cabiddu M, Ghilardi M, Barni S. Risk of anti-EGFR monoclonal antibody-related hypomagnesemia: systematic review and pooled analysis of randomized studies. Expert Opin Drug Safety 11 Suppl 1: S9 –19, 2012. 397. Pfaffenrath V, Wessely P, Meyer C, Isler HR, Evers S, Grotemeyer KH, Taneri Z, Soyka D, Gobel H, Fischer M. Magnesium in the prophylaxis of migraine–a doubleblind placebo-controlled study. Cephalalgia 16: 436 – 440, 1996. 398. Pieper MP. The non-neuronal cholinergic system as novel drug target in the airways. Life Sci 91: 1113–1118, 2012. 399. Piskacek M, Zotova L, Zsurka G, Schweyen RJ. Conditional knockdown of hMRS2 results in loss of mitochondrial Mg2⫹ uptake and cell death. J Cell Mol Med 13: 693–700, 2009.

Physiol Rev • VOL 95 • JANUARY 2015 • www.prv.org

41

Downloaded from on December 26, 2014

365. Nijenhuis T, Hoenderop JG, Bindels RJ. Downregulation of Ca2⫹ and Mg2⫹ transport proteins in the kidney explains tacrolimus (FK506)-induced hypercalciuria and hypomagnesemia. J Am Soc Nephrol 15: 549 –557, 2004.

386. Pardutz A, Vecsei L. Should magnesium be given to every migraineur? No. J Neural Transm 119: 581–585, 2012.


MAGNESIUM IN MAN 400. Pittenger C, Sanacora G, Krystal JH. The NMDA receptor as a therapeutic target in major depressive disorder. CNS Neurol Disorders Drug Targets 6: 101–115, 2007. 401. Pokan R, Hofmann P, von Duvillard SP, Smekal G, Wonisch M, Lettner K, Schmid P, Shechter M, Silver B, Bachl N. Oral magnesium therapy, exercise heart rate, exercise tolerance, and myocardial function in coronary artery disease patients. Br J Sports Med 40: 773–778, 2006. 402. Polok B, Escher P, Ambresin A, Chouery E, Bolay S, Meunier I, Nan F, Hamel C, Munier FL, Thilo B, Megarbane A, Schorderet DF. Mutations in CNNM4 cause recessive cone-rod dystrophy with amelogenesis imperfecta. Am J Hum Genet 84: 259 – 265, 2009. 403. Potter JD, Gergely J. The calcium and magnesium binding sites on troponin and their role in the regulation of myofibrillar adenosine triphosphatase. J Biol Chem 250: 4628 – 4633, 1975. 404. Powell C, Dwan K, Milan SJ, Beasley R, Hughes R, Knopp-Sihota JA, Rowe BH. Inhaled magnesium sulfate in the treatment of acute asthma. Cochrane Database Systematic Rev 12: CD003898, 2012. 405. Powell C, Kolamunnage-Dona R, Lowe J, Boland A, Petrou S, Doull I, Hood K, Williamson P. MAGNEsium Trial In Children (MAGNETIC): a randomised, placebocontrolled trial and economic evaluation of nebulised magnesium sulphate in acute severe asthma in children. Health Technol Assess 17: 1–216, 2013.

422. Rodriguez-Moran M, Guerrero-Romero F. Insulin secretion is decreased in nondiabetic individuals with hypomagnesaemia. Diabetes/Metab Res Rev 27: 590 –596, 2011. 423. Rodriguez-Moran M, Guerrero-Romero F. Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. Diabetes Care 26: 1147–1152, 2003. 424. Romani A. Regulation of magnesium homeostasis and transport in mammalian cells. Arch Biochem Biophys 458: 90 –102, 2007. 425. Rosanoff A, Plesset MR. Oral magnesium supplements decrease high blood pressure (SBP⬎155 mmHg) in hypertensive subjects on anti-hypertensive medications: a targeted meta-analysis. Magnesium Res 26: 93–99, 2013. 426. Rosenecker J, Naundorf S, Rudolph C. Airway surface liquid contains endogenous DNase activity which can be activated by exogenous magnesium. Eur J Med Res 14: 304 –308, 2009. 427. Rowe BH, Camargo CA Jr. The role of magnesium sulfate in the acute and chronic management of asthma. Curr Opin Pulmon Med 14: 70 –76, 2008. 428. Rubin AH, Terasaki M, Sanui H. Magnesium reverses inhibitory effects of calcium deprivation on coordinate response of 3T3 cells to serum. Proc Natl Acad Sci USA 75: 4379 – 4383, 1978. 429. Rubin AH, Terasaki M, Sanui H. Major intracellular cations and growth control: correspondence among magnesium content, protein synthesis, and the onset of DNA synthesis in BALB/c3T3 cells. Proc Natl Acad Sci USA 76: 3917–3921, 1979.

407. Pritchard JA, Pritchard SA. Standardized treatment of 154 consecutive cases of eclampsia. Am J Obstet Gynecol 123: 543–552, 1975.

430. Rubin H. Central role for magnesium in coordinate control of metabolism and growth in animal cells. Proc Natl Acad Sci USA 72: 3551–3555, 1975.

408. Quamme GA. Effect of furosemide on calcium and magnesium transport in the rat nephron. Am J Physiol Renal Fluid Electrolyte Physiol 241: F340 –F347, 1981.

431. Rubin H. The logic of the Membrane, Magnesium, Mitosis (MMM) model for the regulation of animal cell proliferation. Arch Biochem Biophys 458: 16 –23, 2007.

409. Quamme GA. Recent developments in intestinal magnesium absorption. Curr Opin Gastroenterol 24: 230 –235, 2008.

432. Rubin H. The membrane, magnesium, mitosis (MMM) model of cell proliferation control. Magnesium Res 18: 268 –274, 2005.

410. Quamme GA, Smith CM. Magnesium transport in the proximal straight tubule of the rabbit. Am J Physiol Renal Fluid Electrolyte Physiol 246: F544 –F550, 1984.

433. Rude RK. Magnesium depletion and hypermagnesemia. Primer Metab Bone Dis Disorders Miner Metab 1: 2006.

411. Quamme GA, Wong NL, Dirks JH, Roinel N, De Rouffignac C, Morel F. Magnesium handling in the dog kidney: a micropuncture study. Pflügers Arch 377: 95–99, 1978.

434. Rude RK, Gruber HE, Norton HJ, Wei LY, Frausto A, Mills BG. Bone loss induced by dietary magnesium reduction to 10% of the nutrient requirement in rats is associated with increased release of substance P and tumor necrosis factor-alpha. J Nutr 134: 79 – 85, 2004.

412. Quigley GJ, Teeter MM, Rich A. Structural analysis of spermine and magnesium ion binding to yeast phenylalanine transfer RNA. Proc Natl Acad Sci USA 75: 64 – 68, 1978. 413. Qureshi T, Melonakos TK. Acute hypermagnesemia after laxative use. Ann Emergency Med 28: 552–555, 1996. 414. Ramadan NM, Halvorson H, Vande-Linde A, Levine SR, Helpern JA, Welch KM. Low brain magnesium in migraine. Headache 29: 590 –593, 1989. 415. Rasmussen HS, McNair P, Norregard P, Backer V, Lindeneg O, Balslev S. Intravenous magnesium in acute myocardial infarction. Lancet 1: 234 –236, 1986. 416. Regan RF, Jasper E, Guo Y, Panter SS. The effect of magnesium on oxidative neuronal injury in vitro. J Neurochem 70: 77– 85, 1998. 417. Reichold M, Zdebik AA, Lieberer E, Rapedius M, Schmidt K, Bandulik S, Sterner C, Tegtmeier I, Penton D, Baukrowitz T, Hulton SA, Witzgall R, Ben-Zeev B, Howie AJ, Kleta R, Bockenhauer D, Warth R. KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function. Proc Natl Acad Sci USA 107: 14490 –14495, 2010. 418. Reis MA, Latorraca MQ, Carneiro EM, Boschero AC, Saad MJ, Velloso LA, Reyes FG. Magnesium deficiency improves glucose homeostasis in the rat: studies in vivo and in isolated islets in vitro. Br J Nutr 85: 549 –552, 2001. 419. Reis MA, Reyes FG, Saad MJ, Velloso LA. Magnesium deficiency modulates the insulin signaling pathway in liver but not muscle of rats. J Nutr 130: 133–138, 2000. 420. Renkema KY, Alexander RT, Bindels RJ, Hoenderop JG. Calcium and phosphate homeostasis: concerted interplay of new regulators. Ann Med 40: 82–91, 2008. 421. Rodriguez-Hernandez H, Cervantes-Huerta M, Rodriguez-Moran M, Guerrero-Romero F. Oral magnesium supplementation decreases alanine aminotransferase levels in obese women. Magnesium Res 23: 90 –96, 2010.

42

435. Rude RK, Oldham SB, Sharp CF Jr, Singer FR. Parathyroid hormone secretion in magnesium deficiency. J Clin Endocrinol Metab 47: 800 – 806, 1978. 436. Rude RK, Olerich M. Magnesium deficiency: possible role in osteoporosis associated with gluten-sensitive enteropathy. Osteoporosis Int 6: 453– 461, 1996. 437. Rukshin V, Shah PK, Cercek B, Finkelstein A, Tsang V, Kaul S. Comparative antithrombotic effects of magnesium sulfate and the platelet glycoprotein IIb/IIIa inhibitors tirofiban and eptifibatide in a canine model of stent thrombosis. Circulation 105: 1970 –1975, 2002. 438. Runnels LW, Yue L, Clapham DE. TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science 291: 1043–1047, 2001. 439. Sabbagh F, El Tawil Z, Lecerf F, Hulin A, Maurois P, Dartevelle P, Bac P, GermanFattal M. Impact of cyclosporine A on magnesium homeostasis: clinical observation in lung transplant recipients and experimental study in mice. Transplantation 86: 436 – 444, 2008. 440. Sabbagh F, Lecerf F, Maurois P, Bac P, German-Fattal M. Allogeneic activation is attenuated in a model of mouse lung perfused with magnesium-deficient blood. Transplant Immunol 16: 200 –207, 2006. 441. Sahin G, Ertem U, Duru F, Birgen D, Yuksek N. High prevelance of chronic magnesium deficiency in T cell lymphoblastic leukemia and chronic zinc deficiency in children with acute lymphoblastic leukemia and malignant lymphoma. Leukemia Lymphoma 39: 555–562, 2000. 442. Sahni J, Nelson B, Scharenberg AM. SLC41A2 encodes a plasma-membrane Mg2⫹ transporter. Biochem J 401: 505–513, 2007. 443. Salimi MH, Heughebaert JC, Nancollas GH. Crystal growth of calcium phosphates in the presence of magnesium ions. Langmuir 1: 119 –122, 1985.

Physiol Rev • VOL 95 • JANUARY 2015 • www.prv.org

Downloaded from on December 26, 2014

406. Price MA, Tullius TD. 11. Using hydroxyl radical to probe DNA structure. In: Methods in Enzymology, edited by David M. J. Lilley. New York: Academic, 1992, p. 194 –219.


DE BAAIJ ET AL. 444. Sanders NN, Franckx H, De Boeck K, Haustraete J, De Smedt SC, Demeester J. Role of magnesium in the failure of rhDNase therapy in patients with cystic fibrosis. Thorax 61: 962–968, 2006.

465. Shah GM, Alvarado P, Kirschenbaum MA. Symptomatic hypocalcemia and hypomagnesemia with renal magnesium wasting associated with pentamidine therapy in a patient with AIDS. Am J Med 89: 380 –382, 1990.

445. Sanui H, Rubin AH. Membrane bound and cellular cationic changes associated with insulin stimulation of cultured cells. J Cell Physiol 96: 265–278, 1978.

466. Shan Q, Himmerkus N, Hou J, Goodenough DA, Bleich M. Insights into driving forces and paracellular permeability from claudin-16 knockdown mouse. Ann NY Acad Sci 1165: 148 –151, 2009.

446. Sassen MC, Kim SW, Kwon TH, Knepper MA, Miller RT, Frokiaer J, Nielsen S. Dysregulation of renal sodium transporters in gentamicin-treated rats. Kidney Int 70: 1026 –1037, 2006.

468. Shareghi GR, Agus ZS. Magnesium transport in the cortical thick ascending limb of Henle’s loop of the rabbit. J Clin Invest 69: 759 –769, 1982.

447. Satake K, Lee JD, Shimizu H, Uzui H, Mitsuke Y, Yue H, Ueda T. Effects of magnesium on prostacyclin synthesis and intracellular free calcium concentration in vascular cells. Magnesium Res 17: 20 –27, 2004.

469. Shechter M, Hod H, Chouraqui P, Kaplinsky E, Rabinowitz B. Magnesium therapy in acute myocardial infarction when patients are not candidates for thrombolytic therapy. Am J Cardiol 75: 321–323, 1995.

448. Saver JL. Targeting the brain: neuroprotection and neurorestoration in ischemic stroke. Pharmacotherapy 30: 62S– 69S, 2010.

470. Shechter M, Hod H, Marks N, Behar S, Kaplinsky E, Rabinowitz B. Beneficial effect of magnesium sulfate in acute myocardial infarction. Am J Cardiol 66: 271–274, 1990.

449. Saver JL, Kidwell C, Eckstein M, Starkman S. Prehospital neuroprotective therapy for acute stroke: results of the Field Administration of Stroke Therapy-Magnesium (FAST-MAG) pilot trial. Stroke 35: e106 –108, 2004. 450. Scanlan BJ, Tuft B, Elfrey JE, Smith A, Zhao A, Morimoto M, Chmielinska JJ, TejeroTaldo MI, Mak Iu T, Weglicki WB, Shea-Donohue T. Intestinal inflammation caused by magnesium deficiency alters basal and oxidative stress-induced intestinal function. Mol Cell Biochem 306: 59 – 69, 2007. 451. Schelling JR. Fatal hypermagnesemia. Clin Nephrol 53: 61– 65, 2000.

453. Schilsky RL, Anderson T. Hypomagnesemia and renal magnesium wasting in patients receiving cisplatin. Ann Internal Med 90: 929 –931, 1979. 454. Schlingmann KP, Weber S, Peters M, Niemann Nejsum L, Vitzthum H, Klingel K, Kratz M, Haddad E, Ristoff E, Dinour D, Syrrou M, Nielsen S, Sassen M, Waldegger S, Seyberth HW, Konrad M. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nature Genet 31: 166 –170, 2002. 455. Schmitz C, Perraud AL, Johnson CO, Inabe K, Smith MK, Penner R, Kurosaki T, Fleig A, Scharenberg AM. Regulation of vertebrate cellular Mg2⫹ homeostasis by TRPM7. Cell 114: 191–200, 2003. 456. Schneeberger PR, Heizmann CW. Parvalbumin in rat kidney. Purification and localization. FEBS Lett 201: 51–56, 1986. 457. Schoenen J, Sianard-Gainko J, Lenaerts M. Blood magnesium levels in migraine. Cephalalgia 11: 97–99, 1991. 458. Scholl UI, Choi M, Liu T, Ramaekers VT, Hausler MG, Grimmer J, Tobe SW, Farhi A, Nelson-Williams C, Lifton RP. Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. Proc Natl Acad Sci USA 106: 5842–5847, 2009. 459. Schrag D, Chung KY, Flombaum C, Saltz L. Cetuximab therapy and symptomatic hypomagnesemia. J Natl Cancer Inst 97: 1221–1224, 2005. 460. Schultheis PJ, Lorenz JN, Meneton P, Nieman ML, Riddle TM, Flagella M, Duffy JJ, Doetschman T, Miller ML, Shull GE. Phenotype resembling Gitelman’s Syndrome in mice lacking the apical Na⫹-Cl⫺ cotransporter of the distal convoluted tubule. J Biol Chem 273: 29150 –29155, 1998. 461. Schweigel M, Martens H. Magnesium transport in the gastrointestinal tract. Front Biosci 5: D666 – 677, 2000.

472. Shechter M, Sharir M, Labrador MJ, Forrester J, Silver B, Bairey Merz CN. Oral magnesium therapy improves endothelial function in patients with coronary artery disease. Circulation 102: 2353–2358, 2000. 473. Shen B, Nolan JP, Sklar LA, Park MS. Essential amino acids for substrate binding and catalysis of human flap endonuclease 1. J Biol Chem 271: 9173–9176, 1996. 474. Shiga T, Wajima Z, Inoue T, Ogawa R. Magnesium prophylaxis for arrhythmias after cardiac surgery: a meta-analysis of randomized controlled trials. Am J Med 117: 325– 333, 2004. 475. Shindo Y, Fujii T, Komatsu H, Citterio D, Hotta K, Suzuki K, Oka K. Newly developed Mg2⫹-selective fluorescent probe enables visualization of Mg2⫹ dynamics in mitochondria. PloS One 6: e23684, 2011. 476. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 134: 2802–2818, 2011. 477. Simon DB, Bindra RS, Mansfield TA, Nelson-Williams C, Mendonca E, Stone R, Schurman S, Nayir A, Alpay H, Bakkaloglu A, Rodriguez-Soriano J, Morales JM, Sanjad SA, Taylor CM, Pilz D, Brem A, Trachtman H, Griswold W, Richard GA, John E, Lifton RP. Mutations in the chloride channel gene, CLCNKB, cause Bartter’s syndrome type III. Nature Genet 17: 171–178, 1997. 478. Simon DB, Karet FE, Hamdan JM, DiPietro A, Sanjad SA, Lifton RP. Bartter’s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nature Genet 13: 183–188, 1996. 479. Simon DB, Karet FE, Rodriguez-Soriano J, Hamdan JH, DiPietro A, Trachtman H, Sanjad SA, Lifton RP. Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K⫹ channel, ROMK. Nature Genet 14: 152–156, 1996. 480. Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredie D, Milford D, Sanjad S, Lifton RP. Paracellin-1, a renal tight junction protein required for paracellular Mg2⫹ resorption. Science 285: 103–106, 1999. 481. Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, Vaara I, Iwata F, Cushner HM, Koolen M, Gainza FJ, Gitleman HJ, Lifton RP. Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nature Genet 12: 24 –30, 1996.

462. Secil Y, Unde C, Beckmann YY, Bozkaya YT, Ozerkan F, Basoglu M. Blood pressure changes in migraine patients before, during and after migraine attacks. Pain Pract 10: 222–227, 2010.

482. Sinert R, Zehtabchi S, Desai S, Peacock P, Altura BT, Altura BM. Serum ionized magnesium and calcium levels in adult patients with seizures. Scand J Clin Lab Invest 67: 317–326, 2007.

463. Seelig MS, Elin RJ, Antman EM. Magnesium in acute myocardial infarction: still an open question. Can J Cardiol 14: 745–749, 1998.

483. Singh J, Wisdom DM. Second messenger role of magnesium in pancreatic acinar cells of the rat. Mol Cell Biochem 149 –150: 175–182, 1995.

464. Sha Q, Pearson W, Burcea LC, Wigfall DA, Schlesinger PH, Nichols CG, Mercer RW. Human FXYD2 G41R mutation responsible for renal hypomagnesemia behaves as an inward-rectifying cation channel. Am J Physiol Renal Physiol 295: F91–F99, 2008.

484. Singh RB, Pella D, Neki NS, Chandel JP, Rastogi S, Mori H, Otsuka K, Gupta P. Mechanisms of acute myocardial infarction study (MAMIS). Biomed Pharmacotherapy 58 Suppl 1: S111–115, 2004.

Physiol Rev • VOL 95 • JANUARY 2015 • www.prv.org

43

Downloaded from on December 26, 2014

452. Schiffrin EL, Lipman ML, Mann JF. Chronic kidney disease: effects on the cardiovascular system. Circulation 116: 85–97, 2007.

471. Shechter M, Merz CN, Paul-Labrador M, Meisel SR, Rude RK, Molloy MD, Dwyer JH, Shah PK, Kaul S. Oral magnesium supplementation inhibits platelet-dependent thrombosis in patients with coronary artery disease. Am J Cardiol 84: 152–156, 1999.


MAGNESIUM IN MAN 485. Skorodin MS, Tenholder MF, Yetter B, Owen KA, Waller RF, Khandelwahl S, Maki K, Rohail T, D’Alfonso N. Magnesium sulfate in exacerbations of chronic obstructive pulmonary disease. Arch Intern Med 155: 496 –500, 1995. 486. Smith DA, Connick JH, Stone TW. Effect of changing extracellular levels of magnesium on spontaneous activity and glutamate release in the mouse neocortical slice. Br J Pharmacol 97: 475– 482, 1989. 487. Smith LF, Heagerty AM, Bing RF, Barnett DB. Intravenous infusion of magnesium sulphate after acute myocardial infarction: effects on arrhythmias and mortality. Int J Cardiol 12: 175–183, 1986. 488. Song Y, He K, Levitan EB, Manson JE, Liu S. Effects of oral magnesium supplementation on glycaemic control in Type 2 diabetes: a meta-analysis of randomized doubleblind controlled trials. Diabetic Med 23: 1050 –1056, 2006. 489. Song Y, Hsu YH, Niu T, Manson JE, Buring JE, Liu S. Common genetic variants of the ion channel transient receptor potential membrane melastatin 6 and 7 (TRPM6 and TRPM7), magnesium intake, and risk of type 2 diabetes in women. BMC Med Genet 10: 4, 2009. 490. Song Y, Li TY, van Dam RM, Manson JE, Hu FB. Magnesium intake and plasma concentrations of markers of systemic inflammation and endothelial dysfunction in women. Am J Clin Nutr 85: 1068 –1074, 2007. 491. Song Y, Manson JE, Buring JE, Liu S. Dietary magnesium intake in relation to plasma insulin levels and risk of type 2 diabetes in women. Diabetes Care 27: 59 – 65, 2004.

493. Steinert JR, Chernova T, Forsythe ID. Nitric oxide signaling in brain function, dysfunction, and dementia. Neuroscientist 16: 435– 452, 2010. 494. Stendig-Lindberg G, Tepper R, Leichter I. Trabecular bone density in a two year controlled trial of peroral magnesium in osteoporosis. Magnesium Res 6: 155–163, 1993. 495. Stohr W, Paulides M, Bielack S, Jurgens H, Koscielniak E, Rossi R, Langer T, Beck JD. Nephrotoxicity of cisplatin and carboplatin in sarcoma patients: a report from the late effects surveillance system. Pediatr Blood Cancer 48: 140 –147, 2007. 496. Storchheim F. Status epilepticus treated by magnesium sulphate, injected intravenously. JAMA 101: 1313–1314, 1933. 497. Stuiver M, Lainez S, Will C, Terryn S, Gunzel D, Debaix H, Sommer K, Kopplin K, Thumfart J, Kampik NB, Querfeld U, Willnow TE, Nemec V, Wagner CA, Hoenderop JG, Devuyst O, Knoers NV, Bindels RJ, Meij IC, Muller D. CNNM2, encoding a basolateral protein required for renal Mg2⫹ handling, is mutated in dominant hypomagnesemia. Am J Hum Genet 88: 333–343, 2011. 498. Suarez A, Pulido N, Casla A, Casanova B, Arrieta FJ, Rovira A. Impaired tyrosinekinase activity of muscle insulin receptors from hypomagnesaemic rats. Diabetologia 38: 1262–1270, 1995. 499. Sudo GZ, Sanguinetti MC. Intracellular [Mg2⫹] determines specificity of K⫹ channel block by a class III antiarrhythmic drug. J Pharmacol Exp Ther 276: 951–957, 1996. 500. Suh WC, Leirmo S, Record MT Jr. Roles of Mg2⫹ in the mechanism of formation and dissociation of open complexes between Escherichia coli RNA polymerase and the lambda PR promoter: kinetic evidence for a second open complex requiring Mg2⫹. Biochemistry 31: 7815–7825, 1992. 501. Sun Y, Selvaraj S, Varma A, Derry S, Sahmoun AE, Singh BB. Increase in serum Ca2⫹/Mg2⫹ ratio promotes proliferation of prostate cancer cells by activating TRPM7 channels. J Biol Chem 288: 255–263, 2013. 502. Takata Y, Shu XO, Yang G, Li H, Dai Q, Gao J, Cai Q, Gao YT, Zheng W. Calcium intake and lung cancer risk among female nonsmokers: a report from the Shanghai Women’s Health Study. Cancer Epidemiol Biomarkers Prevention 22: 50 –57, 2013. 503. Takaya J, Higashino H, Kobayashi Y. Can magnesium act as a second messenger? Current data on translocation induced by various biologically active substances. Magnesium Res 13: 139 –146, 2000. 504. Takezawa R, Schmitz C, Demeuse P, Scharenberg AM, Penner R, Fleig A. Receptormediated regulation of the TRPM7 channel through its endogenous protein kinase domain. Proc Natl Acad Sci USA 101: 6009 – 6014, 2004.

44

506. Tashiro M, Inoue H, Konishi M. Magnesium homeostasis in cardiac myocytes of mg-deficient rats. PloS One 8: e73171, 2013. 507. Taubert K. [Magnesium in migraine. Results of a multicenter pilot study]. Fortschritte der Medizin 112: 328 –330, 1994. 508. Taylor JS, Vigneron DB, Murphy-Boesch J, Nelson SJ, Kessler HB, Coia L, Curran W, Brown TR. Free magnesium levels in normal human brain and brain tumors: 31P chemical-shift imaging measurements at 1.5 T. Proc Natl Acad Sci USA 88: 6810 – 6814, 1991. 509. Tejero-Taldo MI, Chmielinska JJ, Gonzalez G, Mak IT, Weglicki WB. N-methyl-Daspartate receptor blockade inhibits cardiac inflammation in the Mg2⫹-deficient rat. J Pharmacol Exp Ther 311: 8 –13, 2004. 510. Tejpar S, Piessevaux H, Claes K, Piront P, Hoenderop JG, Verslype C, Van Cutsem E. Magnesium wasting associated with epidermal-growth-factor receptor-targeting antibodies in colorectal cancer: a prospective study. Lancet Oncol 8: 387–394, 2007. 511. Temkin NR, Anderson GD, Winn HR, Ellenbogen RG, Britz GW, Schuster J, Lucas T, Newell DW, Mansfield PN, Machamer JE, Barber J, Dikmen SS. Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial. Lancet Neurol 6: 29 –38, 2007. 512. Teragawa H, Kato M, Yamagata T, Matsuura H, Kajiyama G. Magnesium causes nitric oxide independent coronary artery vasodilation in humans. Heart 86: 212–216, 2001. 513. Teragawa H, Matsuura H, Chayama K, Oshima T. Mechanisms responsible for vasodilation upon magnesium infusion in vivo: clinical evidence. Magnesium Res 15: 241– 246, 2002. 514. Terasaki M, Rubin H. Evidence that intracellular magnesium is present in cells at a regulatory concentration for protein synthesis. Proc Natl Acad Sci USA 82: 7324 –7326, 1985. 515. Thebault S, Alexander RT, Tiel Groenestege WM, Hoenderop JG, Bindels RJ. EGF increases TRPM6 activity and surface expression. J Am Soc Nephrol 20: 78 – 85, 2009. 516. Thebault S, Cao G, Venselaar H, Xi Q, Bindels RJ, Hoenderop JG. Role of the alphakinase domain in transient receptor potential melastatin 6 channel and regulation by intracellular ATP. J Biol Chem 283: 19999 –20007, 2008. 517. Thompson CB, June CH, Sullivan KM, Thomas ED. Association between cyclosporin neurotoxicity and hypomagnesaemia. Lancet 2: 1116 –1120, 1984. 518. Thony B, Neuheiser F, Kierat L, Blaskovics M, Arn PH, Ferreira P, Rebrin I, Ayling J, Blau N. Hyperphenylalaninemia with high levels of 7-biopterin is associated with mutations in the PCBD gene encoding the bifunctional protein pterin-4a-carbinolamine dehydratase and transcriptional coactivator (DCoH). Am J Hum Genet 62: 1302–1311, 1998. 519. Thony B, Neuheiser F, Kierat L, Rolland MO, Guibaud P, Schluter T, Germann R, Heidenreich RA, Duran M, de Klerk JB, Ayling JE, Blau N. Mutations in the pterin4alpha-carbinolamine dehydratase (PCBD) gene cause a benign form of hyperphenylalaninemia. Hum Genet 103: 162–167, 1998. 520. Tietz NW. Clinical Guide to Laboratory Tests. Philadelphia, PA: Saunders, 1995. 521. Tofil NM, Benner KW, Winkler MK. Fatal hypermagnesemia caused by an Epsom salt enema: a case illustration. Southern Medical J 98: 253–256, 2005. 522. Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, McAlister F, Garg AX. Chronic kidney disease and mortality risk: a systematic review. J Am Soc Nephrol 17: 2034 –2047, 2006. 523. Topf JM, Murray PT. Hypomagnesemia and hypermagnesemia. Rev Endocr Metab Disorders 4: 195–206, 2003. 524. Topol EJ, Lerman BB. Hypomagnesemic torsades de pointes. Am J Cardiol 52: 1367– 1368, 1983. 525. Tsang HT, Edwards TL, Wang X, Connell JW, Davies RJ, Durrington HJ, O’Kane CJ, Luzio JP, Reid E. The hereditary spastic paraplegia proteins NIPA1, spastin and spartin are inhibitors of mammalian BMP signalling. Hum Mol Genet 18: 3805– 3821, 2009.

Physiol Rev • VOL 95 • JANUARY 2015 • www.prv.org

Downloaded from on December 26, 2014

492. Sood AK, Handa R, Malhotra RC, Gupta BS. Serum, CSF, RBC & urinary levels of magnesium & calcium in idiopathic generalised tonic clonic seizures. Indian J Med Res 98: 152–154, 1993.

505. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nature Rev Mol Cell Biol 7: 85–96, 2006.


DE BAAIJ ET AL. 526. Turecky L, Kupcova V, Szantova M, Uhlikova E, Viktorinova A, Czirfusz A. Serum magnesium levels in patients with alcoholic and non-alcoholic fatty liver. Bratislavske Lekarske Listy 107: 58 – 61, 2006. 527. Tzivoni D, Banai S, Schuger C, Benhorin J, Keren A, Gottlieb S, Stern S. Treatment of torsade de pointes with magnesium sulfate. Circulation 77: 392–397, 1988.

548. Wang X, Proud CG. Nutrient control of TORC1, a cell-cycle regulator. Trends Cell Biol 19: 260 –267, 2009. 549. Watson JD, Crick FH. Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid. Nature 171: 737–738, 1953.

528. Tzivoni D, Keren A, Cohen AM, Loebel H, Zahavi I, Chenzbraun A, Stern S. Magnesium therapy for torsades de pointes. Am J Cardiol 53: 528 –530, 1984.

550. Weber G, Lea MA, Convery HJ, Stamm NB. Regulation of gluconeogenesis and glycolysis: studies of mechanisms controlling enzyme activity. Adv Enzyme Regul 5: 257– 300, 1967.

529. Van Angelen AA, Glaudemans B, van der Kemp AW, Hoenderop JG, Bindels RJ. Cisplatin-induced injury of the renal distal convoluted tubule is associated with hypomagnesaemia in mice. Nephrol Dialysis Transplantation 28: 879 – 889, 2013.

551. Weber JD, Gutmann DH. Deconvoluting mTOR biology. Cell Cycle 11: 236 –248, 2012.

530. Van Angelen AA, van der Kemp AW, Hoenderop JG, Bindels RJ. Increased expression of renal TRPM6 compensates for Mg2⫹ wasting during furosemide treatment. Clin Kidney J 5: 535–544, 2012.

552. Weglicki WB, Dickens BF, Wagner TL, Chmielinska JJ, Phillips TM. Immunoregulation by neuropeptides in magnesium deficiency: ex vivo effect of enhanced substance P production on circulating T lymphocytes from magnesium-deficient mice. Magnesium Res 9: 3–11, 1996.

531. Van den Bergh WM, Algra A, Rinkel GJ. Electrocardiographic abnormalities and serum magnesium in patients with subarachnoid hemorrhage. Stroke 35: 644 – 648, 2004.

553. Weglicki WB, Mak IT, Phillips TM. Blockade of cardiac inflammation in Mg2⫹ deficiency by substance P receptor inhibition. Circ Res 74: 1009 –1013, 1994.

532. Van den Bergh WM, Algra A, van der Sprenkel JW, Tulleken CA, Rinkel GJ. Hypomagnesemia after aneurysmal subarachnoid hemorrhage. Neurosurgery 52: 276 –281, 2003. 533. Van den Bergh WM, Algra A, van Kooten F, Dirven CM, van Gijn J, Vermeulen M, Rinkel GJ. Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial. Stroke 36: 1011–1015, 2005.

535. Van Laecke S, Van Biesen W, Verbeke F, De Bacquer D, Peeters P, Vanholder R. Posttransplantation hypomagnesemia and its relation with immunosuppression as predictors of new-onset diabetes after transplantation. Am J Transplant 9: 2140 –2149, 2009. 536. Vargas-Caballero M, Robinson HP. Fast and slow voltage-dependent dynamics of magnesium block in the NMDA receptor: the asymmetric trapping block model. J Neurosci 24: 6171– 6180, 2004. 537. Vidair C, Rubin H. Evaluation of Mg2⫹ as an intracellular regulator of uridine uptake. J Cell Physiol 108: 317–325, 1981. 538. Vink R, Nechifor M. Magnesium in the Central Nervous System. Adelaide, Australia: Univ. of Adelaide Press, 2011.

555. Westermaier T, Stetter C, Vince GH, Pham M, Tejon JP, Eriskat J, Kunze E, Matthies C, Ernestus RI, Solymosi L, Roosen K. Prophylactic intravenous magnesium sulfate for treatment of aneurysmal subarachnoid hemorrhage: a randomized, placebo-controlled, clinical study. Crit Care Med 38: 1284 –1290, 2010. 556. Westhof E, Sundaralingam M. Restrained refinement of the monoclinic form of yeast phenylalanine transfer RNA. Temperature factors and dynamics, coordinated waters, and base-pair propeller twist angles. Biochemistry 25: 4868 – 4878, 1986. 557. Weston PG. Magnesium as a sedative. Am J Psychiatry 78: 637– 638, 1922. 558. White RE, Hartzell HC. Effects of intracellular free magnesium on calcium current in isolated cardiac myocytes. Science 239: 778 –780, 1988. 559. Widman L, Wester PO, Stegmayr BK, Wirell M. The dose-dependent reduction in blood pressure through administration of magnesium. A double blind placebo controlled cross-over study. Am J Hypertens 6: 41– 45, 1993. 560. Wilcox ER, Burton QL, Naz S, Riazuddin S, Smith TN, Ploplis B, Belyantseva I, BenYosef T, Liburd NA, Morell RJ, Kachar B, Wu DK, Griffith AJ, Riazuddin S, Friedman TB. Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29. Cell 104: 165–172, 2001.

539. Vink R, van den Heuvel C. Substance P antagonists as a therapeutic approach to improving outcome following traumatic brain injury. Neurotherapeutics 7: 74 – 80, 2010.

561. Wiles ME, Wagner TL, Weglicki WB. Effect of acute magnesium deficiency (MgD) on aortic endothelial cell (EC) oxidant production. Life Sci 60: 221–236, 1997.

540. Voets T, Nilius B, Hoefs S, van der Kemp AW, Droogmans G, Bindels RJ, Hoenderop JG. TRPM6 forms the Mg2⫹ influx channel involved in intestinal and renal Mg2⫹ absorption. J Biol Chem 279: 19 –25, 2004.

562. Wilkinson R, Lucas GL, Heath DA, Franklin IM, Boughton BJ. Hypomagnesaemic tetany associated with prolonged treatment with aminoglycosides. Br Med J 292: 818 – 819, 1986.

541. Volpe SL. Magnesium, the metabolic syndrome, insulin resistance, and type 2 diabetes mellitus. Crit Rev Food Sci Nutr 48: 293–300, 2008.

563. Williams BA, Beatch GN. Magnesium shifts voltage dependence of activation of delayed rectifier I(K) in guinea pig ventricular myocytes. Am J Physiol Heart Circ Physiol 272: H1292–H1301, 1997.

542. Vosgerau H. [Migraine therapy with magnesium glutamate]. Therapie der Gegenwart 112: 640, 1973. 543. Walder RY, Landau D, Meyer P, Shalev H, Tsolia M, Borochowitz Z, Boettger MB, Beck GE, Englehardt RK, Carmi R, Sheffield VC. Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nature Genet 31: 171–174, 2002. 544. Walder RY, Shalev H, Brennan TM, Carmi R, Elbedour K, Scott DA, Hanauer A, Mark AL, Patil S, Stone EM, Sheffield VC. Familial hypomagnesemia maps to chromosome 9q, not to the X chromosome: genetic linkage mapping and analysis of a balanced translocation breakpoint. Hum Mol Genet 6: 1491–1497, 1997. 545. Wang CY, Shi JD, Yang P, Kumar PG, Li QZ, Run QG, Su YC, Scott HS, Kao KJ, She JX. Molecular cloning and characterization of a novel gene family of four ancient conserved domain proteins (ACDP). Gene 306: 37– 44, 2003. 546. Wang JJ, Freeman AI, Gaeta JF, Sinks LF. Unusual complications of pentamidine in the treatment of Pneumocystis carinii pneumonia. J Pediatr 77: 311–314, 1970. 547. Wang M, Tashiro M, Berlin JR. Regulation of L-type calcium current by intracellular magnesium in rat cardiac myocytes. J Physiol 555: 383–396, 2004.

564. Wisdom DM, Salido GM, Baldwin LM, Singh J. The role of magnesium in regulating CCK-8-evoked secretory responses in the exocrine rat pancreas. Mol Cell Biochem 154: 123–132, 1996. 565. Witkowski M, Hubert J, Mazur A. Methods of assessment of magnesium status in humans: a systematic review. Magnesium Res 24: 163–180, 2011. 566. Wolf FI, Fasanella S, Tedesco B, Torsello A, Sgambato A, Faraglia B, Palozza P, Boninsegna A, Cittadini A. Regulation of magnesium content during proliferation of mammary epithelial cells (HC-11). Front Biosci 9: 2056 –2062, 2004. 567. Wolf MT, Dotsch J, Konrad M, Boswald M, Rascher W. Follow-up of five patients with FHHNC due to mutations in the Paracellin-1 gene. Pediatr Nephrol 17: 602– 608, 2002. 568. Wong GK, Poon WS, Chan MT, Boet R, Gin T, Ng SC, Zee BC. Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage (IMASH): a randomized, double-blinded, placebo-controlled, multicenter phase III trial. Stroke 41: 921–926, 2010.

Physiol Rev • VOL 95 • JANUARY 2015 • www.prv.org

45

Downloaded from on December 26, 2014

534. Van den Brandt PA, Smits KM, Goldbohm RA, Weijenberg MP. Magnesium intake and colorectal cancer risk in the Netherlands Cohort Study. Br J Cancer 96: 510 –513, 2007.

554. Weglicki WB, Phillips TM. Pathobiology of magnesium deficiency: a cytokine/neurogenic inflammation hypothesis. Am J Physiol Regul Integr Comp Physiol 263: R734 –R737, 1992.


MAGNESIUM IN MAN 569. Woods KL, Fletcher S, Roffe C, Haider Y. Intravenous magnesium sulphate in suspected acute myocardial infarction: results of the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet 339: 1553–1558, 1992.

584. Zafar S, Hussain A, Liu Y, Lewis D, Inesi G. Specificity of ligand binding to transport sites: Ca2⫹ binding to the Ca2⫹ transport ATPase and its dependence on H⫹ and Mg2⫹. Arch Biochem Biophys 476: 87–94, 2008.

570. Worthington V. Nutritional quality of organic versus conventional fruits, vegetables, and grains. J Altern Complement Med 7: 161–173, 2001.

585. Zaloga GP, Chernow B, Pock A, Wood B, Zaritsky A, Zucker A. Hypomagnesemia is a common complication of aminoglycoside therapy. Surg Gynecol Obstet 158: 561– 565, 1984.

571. Wright FS. Increasing magnitude of electrical potential along the renal distal tubule. Am J Physiol 220: 624 – 638, 1971. 572. Xu JZ, Hall AE, Peterson LN, Bienkowski MJ, Eessalu TE, Hebert SC. Localization of the ROMK protein on apical membranes of rat kidney nephron segments. Am J Physiol Renal Physiol 273: F739 –F748, 1997. 573. Yago MD, Manas M, Singh J. Intracellular magnesium: transport and regulation in epithelial secretory cells. Front Biosci 5: D602– 618, 2000. 574. Yamamoto M, Yamaguchi T, Yamauchi M, Yano S, Sugimoto T. Acute-onset hypomagnesemia-induced hypocalcemia caused by the refractoriness of bones and renal tubules to parathyroid hormone. J Bone Miner Metab 29: 752–755, 2011. 575. Yamazaki D, Funato Y, Miura J, Sato S, Toyosawa S, Furutani K, Kurachi Y, Omori Y, Furukawa T, Tsuda T, Kuwabata S, Mizukami S, Kikuchi K, Miki H. Basolateral Mg2⫹ extrusion via CNNM4 mediates transcellular Mg2⫹ transport across epithelia: a mouse model. PLoS Genet 9: e1003983, 2013. 576. Yan Y, Tian J, Mo X, Zhao G, Yin X, Pu J, Zhang B. Genetic variants in the RAB7L1 and SLC41A1 genes of the PARK16 locus in Chinese Parkinson’s disease patients. Int J Neurosci 121: 632– 636, 2011.

578. Yang L, Frindt G, Palmer LG. Magnesium modulates ROMK channel-mediated potassium secretion. J Am Soc Nephrol 21: 2109 –2116, 2010. 579. Yang Y, Li Q, Ahmad F, Shuaib A. Survival and histological evaluation of therapeutic window of post-ischemia treatment with magnesium sulfate in embolic stroke model of rat. Neurosci Lett 285: 119 –122, 2000. 580. Yasui M, Kihira T, Ota K. Calcium, magnesium and aluminum concentrations in Parkinson’s disease. Neurotoxicology 13: 593– 600, 1992. 581. Yee NS, Zhou W, Liang IC. Transient receptor potential ion channel Trpm7 regulates exocrine pancreatic epithelial proliferation by Mg2⫹-sensitive Socs3a signaling in development and cancer. Disease Models Mechanisms 4: 240 –254, 2011. 582. Young FB, Franciosi S, Spreeuw A, Deng Y, Sanders S, Tam NC, Huang K, Singaraja RR, Zhang W, Bissada N, Kay C, Hayden MR. Low levels of human HIP14 are sufficient to rescue neuropathological, behavioural, and enzymatic defects due to loss of murine HIP14 in Hip14⫺/⫺ mice. PloS One 7: e36315, 2012. 583. Young GL, Jewell D. Interventions for leg cramps in pregnancy. Cochrane Database Systematic Rev CD000121, 2002.

46

587. Zhang W, Iso H, Ohira T, Date C, Tamakoshi A. Associations of dietary magnesium intake with mortality from cardiovascular disease: the JACC study. Atherosclerosis 221: 587–595, 2012. 588. Zhang Z, Yu H, Huang J, Faouzi M, Schmitz C, Penner R, Fleig A. The TRPM6 kinase domain determines the MgATP sensitivity of TRPM7/M6 heteromeric ion channels. J Biol Chem 289: 5217–5227, 2014. 589. Zhou H, Clapham DE. Mammalian MagT1 and TUSC3 are required for cellular magnesium uptake and vertebrate embryonic development. Proc Natl Acad Sci USA 106: 15750 –15755, 2009. 590. Zhou Q, Olinescu RM, Kummerow FA. Influence of low magnesium concentrations in the medium on the antioxidant system in cultured human arterial endothelial cells. Magnesium Res 12: 19 –29, 1999. 591. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Smith SC Jr, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 114: e385– 484, 2006. 592. Zsurka G, Gregan J, Schweyen RJ. The human mitochondrial Mrs2 protein functionally substitutes for its yeast homologue, a candidate magnesium transporter. Genomics 72: 158 –168, 2001. 593. Zumkley H, Bertram HP, Preusser P, Kellinghaus H, Straub C, Vetter H. Renal excretion of magnesium and trace elements during cisplatin treatment. Clin Nephrol 17: 254 –257, 1982. 594. Zuspan FP. Treatment of severe preeclampsia and eclampsia. Clin Obstet Gynecol 9: 954 –972, 1966. 595. Zwillinger L. über die Magnesiumwirkung auf das Herz. Klin Wochenschr 14: 1429 – 1433, 1935.

Physiol Rev • VOL 95 • JANUARY 2015 • www.prv.org

Downloaded from on December 26, 2014

577. Yang L, Arora K, Beard WA, Wilson SH, Schlick T. Critical role of magnesium ions in DNA polymerase beta’s closing and active site assembly. J Am Chem Soc 126: 8441– 8453, 2004.

586. Zaman F, Abreo K. Severe hypermagnesemia as a result of laxative use in renal insufficiency. Southern Med J 96: 102–103, 2003.


Magnesium in Man: Implications for Health and Disease Jeroen H. F. de Baaij, Joost G. J. Hoenderop and RenĂŠ J. M. Bindels Physiol Rev 95:1-46, 2015. doi:10.1152/physrev.00012.2014 You might find this additional info useful... This article cites 574 articles, 168 of which can be accessed free at: /content/95/1/1.full.html#ref-list-1 Updated information and services including high resolution figures, can be found at: /content/95/1/1.full.html Additional material and information about Physiological Reviews can be found at: http://www.the-aps.org/publications/prv

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Magnesium in man  
Magnesium in man